Substituted amides

ABSTRACT

Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson&#39;s disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, and cirrhosis of the liver.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of provisional application 60/428,351filed Apr. 22, 2002 and claims benefit of provisional 60/363,597 Mar.12, 2002.

BACKGROUND OF THE INVENTION

Marijuana (Cannabis sativa L.) and its derivatives have been used forcenturies for medicinal and recreational purposes. A major activeingredient in marijuana and hashish has been determined to beΔ⁹-tetrahydrocannabinol (Δ⁹-THC). Detailed research has revealed thatthe biological action of Δ⁹-THC and other members of the cannabinoidfamily occurs through two G-protein coupled receptors termed CB1 andCB2. The CB1 receptor is primarily found in the central and peripheralnervous systems and to a lesser extent in several peripheral organs. TheCB2 receptor is found primarily in lymphoid tissues and cells. Threeendogenous ligands for the cannabinoid receptors derived fromarachidonic acid have been identified (anandamide, 2-arachidonoylglycerol, and 2-arachidonyl glycerol ether). Each is an agonist withactivities similar to Δ⁹-THC, including sedation, hypothermia,intestinal immobility, antinociception, analgesia, catalepsy,anti-emesis, and appetite stimulation.

The genes for the respective cannabinoid receptors have each beendisrupted in mice. The CB1^(-/-) receptor knockout mice appeared normaland fertile. They were resistant to the effects of Δ⁹-THC anddemonstrated a strong reduction in the reinforcing properties ofmorphine and the severity of withdrawal syndrome. They also demonstratedreduced motor activity and hypoalgesia. The CB2^(-/-) receptor knockoutmice were also healthy and fertile. They were not resistant to thecentral nervous system mediated effects of administered Δ⁹-THC. Therewere some effects on immune cell activation, reinforcing the role forthe CB2 receptor in immune system functions.

Excessive exposure to Δ⁹-THC can lead to overeating, psychosis,hypothermia, memory loss, and sedation. Specific synthetic ligands forthe cannabinoid receptors have been developed and have aided in thecharacterization of the cannabinoid receptors: CP55,940 (J. Pharmacol.Exp. Ther. 1988, 247, 1046-1051); WIN55212-2 (J. Pharmacol. Exp. Ther.1993, 264, 1352-1363); SR141716A (FEBS Lett. 1994, 350, 240-244; LifeSci. 1995, 56, 1941-1947); and SR144528 (J. Pharmacol. Exp. Ther. 1999,288, 582-589). The pharmacology and therapeutic potential forcannabinoid receptor ligands has been reviewed (Exp. Opin. Ther. Patents1998, 8, 301-313; Ann. Rep. Med. Chem., A. Doherty, Ed.; Academic Press,NY 1999, Vol. 34, 199-208; Exp. Opin. Ther. Patents 2000, 10, 1529-1538;Trends in Pharma. Sci. 2000, 21, 218-224). There is at least one CB1modulator characterized as an inverse agonist or an antagonist,N-(1-piperinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide(SR141716A), in clinical trials for treatment of eating disorders atthis time. There still remains a need for potent low molecular weightCB1 modulators that have pharmacokinetic and pharmacodynamic propertiessuitable for use as human pharmaceuticals.

Treatment of asthma with CB1 receptor modulators (such as CB1 inverseagonists) is supported by the finding that presynaptic cannabinoid CB1receptors mediate the inhibition of noradrenaline release (in the guineapig lung) (Europ. J. of Pharmacology, 2001, 431 (2), 237-244).

Treatment of cirrhosis of the liver with CB1 receptor modulators issupported by the finding that a CB1 receptor modulator will reverse thelow blood pressure observed in rats with carbon tetrachloride-inducedliver cirrhosis and will lower the elevated mesenteric blood flow andportal vein pressure (Nature Medicine, 2001, 7 (7), 827-832).

U.S. Pat. No. 5,624,941 and U.S. Pat. No. 6,028,084, PCT ApplicationNos. WO98/43636 and WO98/43635, and EPO Application No. EP-658546disclose substituted pyrazoles having activity against the cannabinoidreceptors.

PCT Application Nos. WO98/31227 and WO98/41519 also disclose substitutedpyrazoles having activity against the cannabinoid receptors.

PCT Application Nos. WO98/37061, WO00/10967, and WO00/10968 disclosediaryl ether sulfonamides having activity against the cannabinoidreceptors.

PCT Application Nos. WO97/29079 and WO99/02499 disclosealkoxy-isoindolones and alkoxy-quinolones as having activity against thecannabinoid receptors.

U.S. Pat. No. 5,532,237 discloses N-benzoyl-indole derivatives havingactivity against the cannabinoid receptors.

U.S. Pat. No. 4,973,587, U.S. Pat. No. 5,013,837, U.S. Pat. No.5,081,122, and U.S. Pat. No. 5,112,820, U.S. Pat. No. 5,292,736 discloseaminoalkylindole derivatives as having activity against the cannabinoidreceptors.

PCT publication WO 01/58869 discloses pyrazoles, pyrroles and imidazolecannabinoid receptor modulatorsuseful for treating respiratory andnon-respiratory leukocyte activation-associated disorders.

PCT publications WO 01/64632, 01/64633, and 01/64634 assigned to Aventisare directed to azetidine derivatives as cannabinoid antagonists.

Schultz, E. M, et al. J. Med Chem. 1967, 10, 717 and Pines, S. H. et al.J. Med. Chem. 1967, 10, 725 disclose maleamic acids affecting plasmacholesterol and penicillin excretion.

The compounds of the present invention are modulators of theCannabinoid-1 (CB1) receptor and are useful in the treatment, preventionand suppression of diseases mediated by the Cannabinoid-1 (CB1)receptor. In particular, compounds of the present invention areantagonists or inverse agonists of the CB1 receptor. The invention isconcerned with the use of these compounds to modulate the Cannabinoid-1(CB1) receptor. As such, compounds of the present invention are usefulas centrally acting drugs in the treatment of psychosis, memorydeficits, cognitive disorders, migraine, neuropathy, neuro-inflammatorydisorders including multiple sclerosis and Guillain-Barre syndrome andthe inflammatory sequelae of viral encephalitis, cerebral vascularaccidents, and head trauma, anxiety disorders, stress, epilepsy,Parkinson's disease, movement disorders, and schizophrenia. Thecompounds are also useful for the treatment of substance abusedisorders, particularly to opiates, alcohol, marijuana, and nicotine.The compounds are also useful for the treatment of eating disorders byinhibiting excessive food intake and the resulting obesity andcomplications associated therewith. The compounds are also useful forthe treatment of constipation and chronic intestinal pseudo-obstruction,as well as for the treatment of asthma, and cirrhosis of the liver.

SUMMARY OF THE INVENTION

The present invention is concerned with novel substituted amides of thegeneral Formula I:

and pharmaceutically acceptable salts thereof which are antagonistsand/or inverse agonists of the Cannabinoid-1 (CB1) receptor and areuseful in the treatment, prevention and suppression of diseases mediatedby the Cannabinoid-1 (CB1) receptor. The invention is concerned with theuse of these novel compounds to selectively antagonize the Cannabinoid-1(CB1) receptor. As such, compounds of the present invention are usefulas centrally acting drugs in the treatment of psychosis, memorydeficits, cognitive disorders, migraine, neuropathy, neuro-inflammatorydisorders including multiple sclerosis and Guillain-Barre syndrome andthe inflammatory sequelae of viral encephalitis, cerebral vascularaccidents, and head trauma, anxiety disorders, stress, epilepsy,Parkinson's disease, movement disorders, and schizophrenia. Thecompounds are also useful for the treatment of substance abusedisorders, particularly to opiates, alcohol, marijuana, and nicotine,including smoking cessation. The compounds are also useful for thetreatment of obesity or eating disorders associated with excessive foodintake and complications associated therewith. The compounds are alsouseful for the treatment of constipation and chronic intestinalpseudo-obstruction. The compounds are also useful for the treatment ofcirrhosis of the liver. The compounds are also useful for the treatmentof asthma.

The present invention is also concerned with treatment of theseconditions, and the use of compounds of the present invention formanufacture of a medicament useful in treating these conditions. Thepresent invention is also concerned with treatment of these conditionsthrough a combination of compounds of formula I and other currentlyavailable pharmaceuticals.

The invention is also concerned with novel compounds of structuralformula I.

The invention is also concerned with pharmaceutical formulationscomprising one of the compounds as an active ingredient.

The invention is further concerned with processes for preparing thecompounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The compounds used in the methods of the present invention arerepresented by the compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein;

-   R¹ is selected from:    -   (1) C₁₋₁₀alkyl,    -   (2) C₃₋₁₀cycloalkyl,    -   (3) C₃₋₁₀cycloalkyl-C₁₋₄alkyl,    -   (4) cycloheteroalkyl,    -   (5) cycloheteroalkyl-C₁₋₄alkyl,    -   (6) aryl,    -   (7) aryl-C₁₋₄alkyl,    -   (8) heteroaryl,    -   (9) heteroaryl-C₁₋₄alkyl,    -   (10) —OR^(d),    -   (11) —NR^(c)R^(d),    -   (12) —NR^(c)C(O)R^(d),    -   (13) —CO₂R^(d), and    -   (14) —C(O)NR^(c)R^(d),    -   wherein each alkyl is optionally substituted with one to four        substituents independently selected from R^(a), and each        cycloalkyl, and cycloheteroalkyl, aryl and heteroaryl are        optionally substituted with one to four substituents        independently selected from R^(b);-   R²is selected from:    -   (1) C₁₋₁₀alkyl,    -   (2) C₃₋₁₀cycloalkyl-C₁₋₄alkyl,    -   (3) cycloheteroalkyl,    -   (4) cycloheteroalkyl-C₁₋₄alkyl,    -   (5) aryl,    -   (6) aryl-C₁₋₄alkyl,    -   (7) aryloxy,    -   (8) arylthio,    -   (9) heteroaryl, and    -   (10) heteroaryl-C₁₋₄alkyl,    -   wherein each alkyl is optionally substituted with one to four        substituents independently selected from R^(a), and each        cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is optionally        substituted with one to four substituents independently selected        from R^(b);-   R³ is selected from:    -   (1) hydrogen, and    -   (2) C₁₋₄alkyl,    -   wherein each alkyl is optionally substituted with one to four        substituents independently selected from R^(a);-   R⁴ is selected from:    -   (1) hydrogen, and    -   (2) C₁₋₄alkyl,    -   wherein each alkyl is optionally substituted with one to four        substituents independently selected from R^(a);-   R⁵ is selected from:    -   (1) C₁₋₁₀alkyl,    -   (2) C₂₋₁₀alkenyl,    -   (3) C₃₋₁₀cycloalkyl-C₁₋₄alkyl,    -   (4) cycloheteroalkyl-C₁₋₄alkyl,    -   (5) aryl-C₁₋₄alkyl,    -   (6) diaryl-C₁₋₄alkyl,    -   (7) aryl-C₁₋₄alkenyl,    -   (8) heteroaryl-C₁₋₄alkyl,    -   (9) —OR^(d), and    -   (10) —NR^(c)R^(d),    -   wherein alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl are        optionally substituted with one to four substituents        independently selected from R^(a) and cycloalkyl,        cycloheteroalkyl, aryl and heteroaryl are optionally substituted        with one to four substituents independently selected from R^(b),        provided that R⁵ is not —CH═CH—COOH;-   each R^(a) is independently selected from:    -   (1) —OR^(d),    -   (2) —NR^(c)S(O)_(m)R^(d),    -   (3) halogen,    -   (4) —SR^(d),    -   (5) —S(O)_(m)NR^(c)R^(d),    -   (6) —NR^(c)R^(d),    -   (7) —C(O)R^(d),    -   (8) —CO₂R^(d),    -   (9) —CN,    -   (10) —C(O)NR^(c)R^(d),    -   (11) —NR^(c)C(O)R^(d),    -   (12) —NR^(c)C(O)OR^(d),    -   (13) —NR^(c)C(O)NR^(c)R^(d),    -   (14) —CF₃,    -   (15) —OCF₃, and    -   (16) cycloheteroalkyl;-   each R^(b) is independently selected from:    -   (1) R^(a),    -   (2) C₁₋₁₀alkyl,    -   (3) oxo,    -   (4) aryl,    -   (5) arylC₁₋₄alkyl,    -   (6) heteroaryl, and    -   (7) heteroarylC₁₋₄alkyl,-   R^(c) and R^(d) are independently selected from:    -   (1) hydrogen,    -   (2) C₁₋₁₀alkyl,    -   (3) C₂₋₁₀alkenyl,    -   (4) cycloalkyl,    -   (5) cycloalkyl-C₁₋₁₀alkyl;    -   (6) cycloheteroalkyl,    -   (7) cycloheteroalkyl-C₁₋₁₀alkyl;    -   (8) aryl,    -   (9) heteroaryl,    -   (10) aryl-C₁₋₁₀alkyl, and    -   (11) heteroaryl-C₁₋₁₀alkyl, or-   R^(c) and R^(d) together with the atom(s) to which they are attached    form a heterocyclic ring of 4 to 7 members containing 0-2 additional    heteroatoms independently selected from oxygen, sulfur and N—R^(g),-   each R^(c) and R^(d) may be unsubstituted or substituted with one to    three substituents selected from R^(h);-   each R^(g) is independently selected from    -   (1) C₁₋₁₀alkyl, and    -   (2) —C(O)R^(c);-   each R^(h) is independently selected from:    -   (1) halogen,    -   (2) C₁₋₁₀alkyl,    -   (3) —O—C₁₋₄alkyl,    -   (4) —S—C₁₋₄alkyl,    -   (5) —CN,    -   (6) —CF₃, and    -   (7) —OCF₃, and-   m is selected from 1 and 2.

In one embodiment of the present invention, when R¹ is unsubstitutedphenyl, R² is unsubstituted benzyl, R³ is unsubstituted methyl, and R⁴is hydrogen, then R⁵ is neither unsubstituted methyl nor unsubstitutedphenyl; and

-   -   when R¹ is unsubstituted benzyl, R² is unsubstituted phenyl, R³        is unsubstituted methyl, and R⁴ is hydrogen, then R⁵ is neither        unsubstituted methyl nor unsubstituted phenyl; and    -   when R¹ is unsubstituted phenyl, R² is 4-methoxybenzyl, R³ is        methyl, R⁴ is hydrogen, then R⁵ is not 3,4,5,-trimethoxyphenyl;        and    -   when R¹ is 4-methoxybenzyl, R² is unsubstituted phenyl, R³ is        methyl, R⁴ is hydrogen, then R⁵ is not 3,4,5,-trimethoxyphenyl.

In another embodiment of the present invention, when R¹ is unsubstitutedphenyl, R² is unsubstituted benzyl, R³ is unsubstituted methyl, and R⁴is hydrogen, then R⁵ is not unsubstituted methyl; and

-   -   when R¹ is unsubstituted benzyl, R² is unsubstituted phenyl, R³        is unsubstituted methyl, and R⁴ is hydrogen, then R⁵ is not        unsubstituted methyl.

In one embodiment of the present invention, R¹ is selected from:

-   -   (1) C₁₋₁₀alkyl,    -   (2) C₃₋₁₀cycloalkyl,    -   (3) C₃₋₁₀cycloalkyl-C₁₋₄alkyl,    -   (4) cycloheteroalkyl,    -   (5) cycloheteroalkyl-C₁₋₄alkyl,    -   (6) aryl,    -   (7) aryl-C₁₋₄alkyl,    -   (8) heteroaryl,    -   (9) heteroaryl-C₁₋₄alkyl,    -   (10) —OR^(d),    -   (11) —NR^(c)R^(d),    -   (12) —NR^(c)C(O)R^(d),    -   (13) —CO₂R^(d), and    -   (14) —C(O)NR^(c)R^(d),    -   wherein each alkyl is optionally substituted with one to three        substituents independently selected from R^(a), and each        cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is optionally        substituted with one to three substitutents independently        selected from R^(b).

In one class of this embodiment of the present invention, R¹ is selectedfrom:

-   -   (1) C₁₋₅alkyl,    -   (2) cycloalkyl,    -   (3) cycloheteroalkyl,    -   (4) aryl,    -   (5) aryl-C₁₋₄alkyl,    -   (6) heteroaryl,    -   (7) heteroaryl-C₁₋₄alkyl,    -   (8) C₁₋₅alkyloxy,    -   (9) —OR^(d), and    -   (10) —CO₂R^(d),        wherein each alkyl is optionally substituted with one to three        substituents independently selected from R^(a), and each aryl        and heteroaryl is optionally substituted with one to three        substitutents independently selected from R^(b).

In a subclass of this class of the present invention, R¹ is selectedfrom:

-   -   (1) C₁₋₅alkyl,    -   (2) cyclobutyl,    -   (3) cyclopentyl,    -   (4) cyclohexyl,    -   (5) pyrrolidinyl,    -   (6) phenyl,    -   (7) phenyl-C₁₋₄alkyl,    -   (8) pyridyl, and    -   (9) pyridyl-C₁₋₄alkyl,        wherein each alkyl is optionally substituted with one or two        R^(a) substituents and each phenyl or pyridyl is independently        with one to three R^(b) substituents.

In another subclass of this class of the present invention, R¹ isselected from:

-   -   (1) C₁₋₅alkyl,    -   (2) cyclobutyl,    -   (3) cyclopentyl,    -   (4) cyclohexyl,    -   (5) pyrrolidinyl,    -   (6) phenyl,    -   (7) phenyl-C₁₋₄alkyl,    -   (8) pyridyl, and    -   (9) pyridyl-C₁₋₄alkyl,        wherein each phenyl and pyridyl is optionally substituted with        one or two substituents selected from halogen, methyl,        trifluoromethyl, cyano and methoxy, and each pyridyl is        optionally present as the N-oxide.

In yet another subclass of this class of the present invention, R¹ isselected from:

-   -   (1) ethyl,    -   (2) isopropyl,    -   (3) isobutyl,    -   (4) n-propyl,    -   (5) n-pentyl,    -   (6) cyclopentyl,    -   (7) pyrrolidinyl,    -   (8) phenyl,    -   (9) phenyl-C₁₋₄alkyl,    -   (10) pyridyl,    -   (11) pyridyl-C₁₋₄alkyl,    -   (12) triazolyl,    -   (13) ethyloxy,    -   (14) propyloxy,    -   (15) butyloxy,    -   (16) n-pentyloxy,    -   (17) benzyloxylcarbonyl,    -   (18) cyclopentylmethyloxy, and    -   (19) cyclobutylmethyloxy,        wherein each phenyl and heteroaryl is optionally substituted        with one or two substituents selected from halogen, and methoxy,        and each pyridyl is optionally present as the N-oxide.

In another embodiment of the present invention, R² is selected from:

-   -   (1) C₁₋₁₀alkyl,    -   (2) C₃₋₁₀cycloalkyl-C₁₋₄alkyl,    -   (3) cycloheteroalkyl,    -   (4) cycloheteroalkyl-C₁₋₄alkyl,    -   (5) aryl,    -   (6) aryl-C₁₋₄alkyl,    -   (7) aryloxy,    -   (8) arylthio,    -   (9) heteroaryl, and    -   (10) heteroaryl-C₁₋₄alkyl,    -   wherein each alkyl is optionally substituted with one to three        substituents independently selected from R^(a), and each        cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is optionally        substituted with one to three substituents independently        selected from R^(b).

In one class of this embodiment of the present invention, R² is selectedfrom:

-   -   (1) C₁₋₄alkyl,    -   (2) aryl,    -   (3) aryl-C₁₋₄alkyl,    -   (4) aryloxy,    -   (5) arylthio,    -   (6) heteroaryl, and    -   (7) heteroaryl-C₁₋₄alkyl,    -   wherein each alkyl is optionally substituted with one R^(a)        substituent, and each aryl and heteroaryl is optionally        substituted with one to three substituents independently        selected from R^(b).

In a subclass of this class of the present invention, aryl is phenyl andheteroaryl is pyridyl in R².

In another subclass of this class of the present invention, R² isselected from:

-   -   (1) isopropyl,    -   (2) isobutyl,    -   (3) n-propyl,    -   (4) phenyl,    -   (5) benzyl,    -   (6) phenylethyl,    -   (7) 3-phenylpropyl,    -   (8) 2-phenylpropyl,    -   (9) phenoxy,    -   (10) phenylthio, and    -   (11) pyridylmethyl,        wherein each aryl and heteroaryl is optionally substituted with        one or two R^(b) substituents selected from halogen,        trifluoromethyl, cyano, methoxycarbonyl, and methoxy.

In yet another embodiment of the present invention, R² is selected from:

-   -   (1) C₁₋₁₀alkyl,    -   (2) C₃₋₁₀cycloalkyl-C₁₋₄alkyl,    -   (3) cycloheteroalkyl,    -   (4) cycloheteroalkyl-C₁₋₄alkyl,    -   (5) aryl,    -   (6) aryl-C₁₋₄alkyl,    -   (7) aryloxy,    -   (8) arylthio,    -   (9) arylamino,    -   (10) heteroaryl, and    -   (11) heteroaryl-C₁₋₄alkyl,    -   wherein each alkyl is optionally substituted with one to four        substituents independently selected from R^(a), and each        cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is optionally        substituted with one to four substituents independently selected        from R^(b).

In another embodiment of the present invention, R³ is selected from:

-   -   (1) hydrogen, and    -   (2) C₁₋₄alkyl,        wherein alkyl is optionally substituted with one or two        substituents selected from R^(a).

In one class of this embodiment of the present invention, R³ is selectedfrom:

-   -   (1) hydrogen,    -   (2) methyl,    -   (3) ethyl, and    -   (4) isopropyl.

In one subclass of this class of the present invention, R³ is selectedfrom hydrogen, methyl and ethyl.

In another subclass of this class of the present invention, R³ ismethyl.

In another embodiment of the present invention, R⁴ is selected from:

-   -   (1) hydrogen, and    -   (2) C₁₋₄alkyl,        wherein alkyl is optionally substituted with one or two        substituents selected from R^(a).

In one class of this embodiment of the present invention, R⁴ is selectedfrom:

-   -   (1) hydrogen, and    -   (2) methyl.        In one subclass of this class, R⁴ is hydrogen.

In another embodiment of the present invention, R⁵ is selected from:

-   -   (1) C₁₋₁₀alkyl,    -   (2) C₂₋₁₀alkenyl,    -   (3) C₃₋₁₀cycloalkyl-C₁₋₄alkyl,    -   (4) cycloheteroalkyl-C₁₋₄alkyl,    -   (5) aryl-C₁₋₄alkyl,    -   (6) diaryl-C₁₋₄alkyl,    -   (7) aryl-C₁₋₄alkenyl,    -   (8) heteroaryl-C₁₋₄alkyl,    -   (9) —OR^(d), and    -   (10) —NR^(c)R^(d),        wherein each alkyl or alkenyl is optionally substituted with one        or two substituents independently selected from R^(a), and each        cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is each        optionally substituted with on to three substituents        independently selected from R^(b), provided that R⁵ is not        —CH═CH—COOH.

In one class of this embodiment of the present invention, R⁵ is selectedfrom:

-   -   (1) C₁₋₈alkyl,    -   (2) C₂₋₈alkenyl,    -   (3) cycloheteroalkyl-C₁₋₄alkyl,    -   (4) aryl-C₁₋₄alkyl,    -   (5) diaryl-C₁₋₄alkyl,    -   (6) aryl-C₁₋₄alkenyl,    -   (7) heteroaryl-C₁₋₄alkyl,    -   (8) —OR^(d), and    -   (9) —NR^(c)R^(d),        wherein each alkyl or alkenyl is optionally substituted with one        or two substituents independently selected from R^(a), and each        cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is each        optionally substituted with on to three substituents        independently selected from R^(b), provided that R⁵ is not        —CH═CH—COOH.

In one subclass of this embodiment of the present invention, R⁵ isselected from:

-   -   (1) C₁₋₈alkyl,    -   (2) C₂₋₈alkenyl,    -   (3) cycloheteroalkyl-C₁₋₄alkyl,    -   (4) aryl-C₁₋₄alkyl,    -   (5) diaryl-C₁₋₄alkyl,    -   (6) aryl-C₁₋₄alkenyl,    -   (7) heteroaryl-C₁₋₄alkyl,    -   (8) —OR^(d), and    -   (9) —NR^(c)R^(d),        wherein each alkyl or alkenyl is optionally substituted with one        or two substituents independently selected from R^(a), and each        cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is each        optionally substituted with one to three substituents        independently selected from R^(b) and wherein cycloheteroalkyl        is selected from pyrrolidinyl, 2H-phthalazinyl,        azabicyclo[2.2.1]heptanyl, benzoxapinyl, morpholinyl,        piperazinyl, dihydroimidazo[2,1-b]thiazolyl, and piperidinyl;        aryl is selected from phenyl and naphthyl; and heteroaryl is        selected from pyridyl, pyrazolyl, triazolyl, benzothiazolyl,        benzoxazolinyl, isoxazolyl, indolyland thiazolyl, provided that        R⁵ is not —CH═CH—COOH.

In a subclass of this class of the present invention, R⁵ is selectedfrom:

-   -   (1) isopropyl,    -   (2) isobutyl,    -   (3) t-butyl,    -   (4) pentyl,    -   (5) benzyl,    -   (6) α-hydroxy-benzyl,    -   (7) α-methoxy-benzyl,    -   (8) α-hydroxy-diphenyl-methyl,    -   (9) 3-(aminosulfonyl)-propyl,    -   (10) 5-(t-butyloxycarbonylamino)-pentyl,    -   (11) anilino,    -   (12) anilino-methyl,    -   (13) t-butoxy,    -   (14) phenoxy,    -   (15) benzyloxy,    -   (16) 1-naphthyl-methyl,    -   (17) phenyl-ethyl,    -   (18) 3-phenyl-propyl,    -   (19) 3,3-diphenyl-propyl,    -   (20) 2-phenyl-ethylene,    -   (21) 1-phenyl-propyl,    -   (22) methoxymethyl,    -   (23) 3-benzoyl-propyl,    -   (24) 7-benzoyl-heptyl,    -   (25) 2-t-butoxy-ethyl,    -   (26) phenoxy-methyl,    -   (27) 1-(phenoxy)-ethyl,    -   (28) 2-(phenoxy)-isopropyl,    -   (29) 2-(pyridyloxy)-isopropyl,    -   (30) 2-(pyrimidinyloxy)-isopropyl,    -   (31) 2-(pyridazinyloxy)-isopropyl,    -   (32) cyclopropyl-methyl,    -   (33) cyclopentyl-methyl,    -   (34) 2-(cyclohexyloxy)-isopropyl,    -   (35) (1-indanone)-3-methyl,    -   (36) (2-thiazolyl)-S-methyl,    -   (37) (2-benzothiazolyl)-S-methyl,    -   (38) (2-benzoxazolyl)-S-methyl,    -   (39) benztriazolyl-methyl,    -   (40) 2-(benzothiazolyl)-ethyl,    -   (41) isoxazolyl-methyl,    -   (42) thiazolyl-methyl,    -   (43) triazolyl-methyl,    -   (44) 2-(triazolyl)-ethyl,    -   (45) pyrazolyl-methyl,    -   (46) 2-(pyrazolyl)-ethyl, and    -   (47) (3-(1-oxo-isoindolyl))-methyl;        wherein each alkyl or alkenyl is optionally substituted with one        or two substituents independently selected from R^(a), and each        cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is each        optionally substituted with on to three substituents        independently selected from R^(b).

In yet another subclass of this class of the invention, R⁵ is C₁₋₈alkylsubstituted with —OR^(d).

In one embodiment of the present invention, each R^(a) is independentlyselected from:

-   -   (1) —OR^(d),    -   (2) —NHS(O)_(m)R^(d),    -   (3) halogen,    -   (4) —SR^(d),    -   (5) —S(O)_(m)NHR^(d),    -   (6) —NR^(c)R^(d),    -   (7) —C(O)R^(d),    -   (8) —CO₂R^(d),    -   (9) —CN,    -   (10) —C(O)NHR^(d),    -   (11) —NHC(O)R^(d),    -   (12) —NHC(O)OR^(d),    -   (13) —NHC(O)NHR^(d),    -   (14) —CF₃,    -   (15) —OCF₃, and    -   (16) cycloheteroalkyl.

In one class of this embodiment of the present invention, each R^(a) isindependently selected from:

-   -   (1) —OR^(d),    -   (2) —NHS(O)₂R^(d),    -   (3) halogen,    -   (4) —SR^(d),    -   (5) —S(O)₂NH₂,    -   (6) —NHR^(d),    -   (7) —N(CH₂CH₃)R^(d),    -   (8) —C(O)R^(d),    -   (9) —CO₂H,    -   (10) —CN,    -   (11) —C(O)NHR^(d),    -   (12) —NHC(O)R^(d),    -   (13) —NHC(O)OR^(d),    -   (14) —NHC(O)NHR^(d),    -   (15) —CF₃,    -   (16) —OCF₃, and    -   (17) cycloheteroalkyl.

In another embodiment of the present invention, each R^(a) isindependently selected from:

-   -   (1) —OR^(d),    -   (2) —NR^(c)S(O)_(m)R^(d),    -   (3) halogen,    -   (4) S(O)_(m)R^(d),    -   (5) —S(O)_(m)NR^(c)R^(d),    -   (6) —NR^(c)R^(d),    -   (7) —C(O)R^(d),    -   (8) —CO₂R^(d),    -   (9) —CN,    -   (10) —C(O)NR^(c)R^(d),    -   (11) —NR^(c)C(O)R^(d),    -   (12) —NR^(c)C(O)OR^(d),    -   (13) —NR^(c)C(O)NR^(c)R^(d),    -   (14) —CF₃,    -   (15) —OCF₃, and    -   (16) cycloheteroalkyl.

In one embodiment of the present invention, each R^(b) is independentlyselected from:

-   -   (1) —OR^(d),    -   (2) —NHS(O)_(m)R^(d),    -   (3) halogen,    -   (4) —SR^(d),    -   (5) —S(O)_(m)NHR^(d),    -   (6) —NHR^(d),    -   (7) —C(O)R^(d),    -   (8) —CO₂R^(d),    -   (9) —CN,    -   (10) —C(O)NR^(c)R^(d),    -   (11) —NHC(O)R^(d),    -   (12) —NHC(O)OR^(d),    -   (13) —NHC(O)NR^(c)R^(d),    -   (14) —CF₃,    -   (15) —OCF₃,    -   (16) cycloheteroalkyl;    -   (17) C₁₋₁₀alkyl,    -   (18) oxo,    -   (19) aryl,    -   (20) arylC₁₋₄alkyl,    -   (21) heteroaryl, and    -   (22) heteroarylC₁₋₄alkyl.

In one class of this embodiment of the present invention, each R^(b) isindependently selected from:

-   -   (1) OR^(d),    -   (2) halogen,    -   (3) —CN,    -   (4) —CF₃,    -   (5) —OCF₃,    -   (6) cycloheteroalkyl;    -   (7) C₁₋₄alkyl,    -   (8) oxo,    -   (9) phenyl,    -   (10) benzyl, and    -   (11) heteroaryl.

In one embodiment of the present invention, each R^(c) is independentlyselected from:

-   -   (1) hydrogen, and    -   (2) C₁₋₄alkyl, and

-   each R^(d) is independently selected from:    -   (1) hydrogen,    -   (2) C₁₋₄alkyl,    -   (3) C₂₋₆ alkenyl,    -   (4) cycloalkyl,    -   (5) cycloalkyl-C₁₋₄alkyl,    -   (6) cycloheteroalkyl,    -   (7) cycloheteroalkyl-C₁₋₄alkyl,    -   (8) phenyl,    -   (9) heteroaryl,    -   (10) phenyl-C₁₋₄alkyl, and    -   (11) heteroaryl-C₁₋₄alkyl, or

-   R^(c) and R^(d) together with the atom(s) to which they are attached    form a heterocyclic ring of 4 to 7 members containing 0-2 additional    heteroatoms independently selected from oxygen, sulfur and N—R^(g),

-   each R^(c) and R^(d) may be unsubstituted or substituted with one to    three substituents selected from R^(h).

In one class of this embodiment of the present invention, each R^(c) isindependently selected from:

-   -   (1) hydrogen, and    -   (2) C₁₋₄alkyl, and        each R^(d) is independently selected from:    -   (1) hydrogen,    -   (2) C₁₋₅alkyl,    -   (3) —CH₂CH═CH₂,    -   (4) cyclohexyl,    -   (5) cyclopentyl,    -   (6) cyclopropyl,    -   (7) cyclobutylmethyl,    -   (8) cyclopentylmethyl,    -   (9) cyclohexylmethyl,    -   (10) pyrrolidinyl,    -   (11) phenyl,    -   (12) thiazolyl,    -   (13) pyridyl,    -   (14) benzothiazolyl,    -   (15) benzoxazolyl,    -   (16) triazolyl,    -   (17) benzyl, and    -   (18) pyridyl-methyl-, or        R^(c) and R^(d) together with the atom(s) to which they are        attached form a piperidinyl ring,        each R^(c) and R^(d) may be unsubstituted or substituted with        one to three substituents selected from R^(h).

In one embodiment of the present invention, each R^(g) is independentlyselected from:

-   -   (1) C₁₋₄alkyl, and    -   (2) —C(O)C₁₋₄alkyl.

In one class of this embodiment, each R^(g) is methyl or methylcarbonyl.

In one subclass of this class, each R^(g) is methyl.

In one embodiment of the present invention, each R^(h) is independentlyselected from:

-   -   (1) halogen,    -   (2) C₁₋₄alkyl,    -   (3) —O—C₁₋₄alkyl,    -   (4) —S—C₁₋₄alkyl,    -   (5) —CN,    -   (6) —CF₃, and    -   (7) —OCF₃.

In one class of this embodiment, each R^(h) is independently selectedfrom:

-   -   (1) halogen,    -   (2) methyl,    -   (3) methoxy,    -   (4) methylthio-,    -   (5) —CN,    -   (6) —CF₃, and    -   (7) —OCF₃.        In another embodiment of the present invention, each R^(h) is        independently selected from:    -   (1) halogen,    -   (2) C₁₋₁₀alkyl,    -   (3) —O C₁₋₄alkyl,    -   (4) —S(O)_(m)C₁₋₄alkyl,    -   (5) —CN,    -   (6) —CF₃, and    -   (7) —OCF₃.

In a subclass of this embodiment, each R^(h) is independently selectedfrom:

-   -   (1) halogen,    -   (2) C₁₋₃alkyl,    -   (3) —SO₂CH₃    -   (4) —CN, and    -   (5) —CF₃.

In one embodiment of the present invention, m is two.

In another embodiment of the present invention, m is selected from 0, 1,and 2.

Particular novel compounds which may be employed in the methods, usesand compositions of the present invention, include:

-   (1)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(pyrazol-1-yl)acetamide,    trifluoroacetic acid salt;-   (2)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(1,2,4-triazol-1-yl)acetamide,    trifluoroacetic acid salt;-   (3)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(benzothiazole-2-thio)acetamide,    trifluoroacetic acid salt;-   (4)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(benzoxazole-2-thio)acetamide,    trifluoroacetic acid salt;-   (5)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(benzoxazolin-2-on-3-yl)acetamide;-   (6)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(4-methyl-2H-phthalazin-1-on-2-yl)acetamide;-   (7)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(2H-phthalazin-1-on-4-yl)propanamide;-   (8)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(3,5-dimethyl-1,2,4-triazol-1    -yl)acetamide, trifluoroacetic acid salt;-   (9)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(2-methyl-thiazol-4-yl)acetamide,    trifluoroacetic acid salt;-   (10)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(1-(4-phenyl-pyrrolidin-2-on-1-yl))acetamide;-   (11)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(3,5-dimethyl-pyrazol-1-yl)acetamide,    trifluoroacetic acid salt;-   (12)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(3-methyl-pyrazol-1-yl)acetamide,    trifluoroacetic acid salt;-   (13)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(isoindolin-1-on-3-yl)acetamide;-   (14)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(3,5-dimethyl-isoxazol-4-yl)acetamide,    trifluoroacetic acid salt;-   (15)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-3-(3,5-dimethyl-pyrazol-1-yl)propanamide,    trifluoroacetic acid salt;-   (16)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(3-methyl-pyrazol-1-yl)acetamide,    trifluoroacetic acid salt;-   (17)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(4-(imidazolidin-2-on-1-yl)phenyl)acetamide;-   (18)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(5-methyl-1,2,4-triazol-3-yl)acetamide,    trifluoroacetic acid salt;-   (19)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-5-(2-methyl)phenyl-5-oxo-pentanamide;-   (20)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-3-(benzothiazol-2-yl)propanamide,    trifluoroacetic acid salt;-   (21)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-3-(aza-bicyclo[2.2.1]heptan-2-yl)propanamide,    trifluoroacetic acid salt;-   (22)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetamide;-   (23)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(benzotriazol-2-yl)acetamide,    trifluoroacetic acid salt;-   (24)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(4-methyl-thiazol-2-yl-thio)acetamide,    trifluoroacetic acid salt;-   (25)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(4,4-diphenyl)butanamide;-   (26)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-3-(1,2,4-triazol-1-yl)propanamide,    trifluoroacetic acid salt;-   (27)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(imidazo[2,1-b][1,3]thiazol-6-yl)acetamide,    trifluoroacetic acid salt;-   (28)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-3-(3,5-dichlorophenyl)propanamide;-   (29)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-4-(3,5-dichlorophenyl)butanamide;-   (30)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-3-(t-butoxy)propanamide;-   (31)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-4-(2,3-dihydro-indol-1-yl)butanamide;-   (32)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-3-(1-methyl-pyrazol-5-yl)propanamide,    trifluoroacetic acid salt;-   (33)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-3-(4-t-butoxyphenyl)propanamide;-   (34)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-3-(3,5-dimethylphenyl)propanamide;-   (35)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(5-methyl-pyrazol-1-yl)acetamide,    trifluoroacetic acid salt;-   (36)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(4-methyl-1,2,4-triazol-3-yl-thio)acetamide,    trifluoroacetic acid salt;-   (37)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(2,3,4,5-tetrahydro-1,4-benzoxazepin-4-yl)acetamide,    trifluoroacetic acid salt;-   (38)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-6-(t-butyloxycarbonylamino)hexanamide;-   (39)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(5,6-dihydro-imidazo[2,1-b]thiazol-3-yl)acetamide,    trifluoroacetic acid salt;-   (40)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(morpholin-4-yl)-2-(3-pyridyl)acetamide,    trifluoroacetic acid salt;-   (41)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-4-(aminosulfonyl)-butanamide;-   (42)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(4-phenyl-piperazin-1-yl)acetamide,    trifluoroacetic acid salt;-   (43) N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-trans-cinnamamide;-   (44)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-9-phenyl-9-oxo-nonanamide;-   (45)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-phenyl-butanamide;-   (46)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-cyclopropyl-acetamide;-   (47)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(1-naphthyl)-acetamide;-   (48)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(5-methoxy-1-indanon-3-yl)-acetamide;-   (49)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-phenoxy-acetamide;-   (50)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-3-(4-hydroxyphenyl)-propanamide;-   (51) N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-hexanamide;-   (52)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-cyclopentyl-acetamide;-   (53) N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-ethoxy-acetamide;-   (54)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-3-methyl-butanamide;-   (55)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-3-(1-t-butoxycarbonyl-piperidin-4-yl)-propanamide;-   (56)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-(3-chlorophenyl)-acetamide;-   (57)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-3-(4-chlorophenyl)-propanamide;-   (58)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-hydroxy-2-phenyl-acetamide;-   (59)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-hydroxy-2-(4-methoxy-phenyl)-acetamide;-   (60)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-methoxy-2-phenyl-acetamide;-   (61)    N-[2,3-bis(4-chlorophenyl)-1-methyl-propyl]-2-hydroxy-2,2-diphenyl-acetamide;-   (62)    N-[2,3-Bis(4-Chlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (63)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(4-cyclohexyloxy)-2-methylpropanamide;-   (64)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(2-fluorophenyloxy)-2-methylpropanamide;-   (65)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(3-fluorophenyloxy)-2-methylpropanamide;-   (66)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(3,4-difluorophenyloxy)-2-methylpropanamide;-   (67)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (68)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(2-chlorophenyloxy)-2-methylpropanamide;-   (69)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (70)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(3-cyanophenyloxy)-2-methylpropanamide;-   (71)    N-[3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (72)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-phenyloxy-2-methylpropanamide;-   (73)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (74)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2,2-dimethylpropanamide;-   (75)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-4-chlorophenylcarbamate;-   (76)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-N′-(4-chlorophenyl)urea;-   (77) N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]benzyl carbamate;-   (78)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-tert-butylcarbamate^(c);-   (79)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(3-pyridyloxy)-2-methylpropanamide;-   (80)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(2-pyridylox)-2-methylbutanamide;-   (81)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;-   (82)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(4-pyridyloxy)-2-methylpropanamide;-   (83)    N-[3,4-Bis(4-Chlorophenyl)-1-methylpropyl]-2-(2-methoxyphenyloxy)-propenamide;-   (84)    N-[3,4-Bis(4-Chlorophenyl)-1-methylpropyl]-2-(2-methoxyphenyloxy)-propenamide;-   (85)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-fluorophenyloxy)-2-methylpropanamide;-   (86)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-fluorophenyloxy)-2-methylpropanamide;-   (87)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,4-difluorophenyloxy)-2-methylpropanamide;-   (88)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (89)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-chlorophenyloxy)-2-methylpropanamide;-   (90)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (91)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-cyclohexyloxy-2-methylpropanamide;-   (92)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (93)    N-[3-(4-Chlorophenyl)-2-(2-fluorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (94)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (95)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl)]-2-methyl-2-phenylpropanamide;-   (96)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;-   (97)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (98)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-pyridyloxy)-2-methylpropanamide;-   (99)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylbutanamide;-   (100)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;-   (101)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-pyridyloxy)-2-methylpropanamide;-   (102)    N-[2-(4-Chlorophenyl)-1-methyl-3-phenylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (103)    N-[2-(4-Chlorophenyl)-1-methyl-3-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (104)    N-[3-(4-Methoxycarbonylphenyl)-1-methyl-2-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (105)    N-[3-(4-Methoxycarbonylphenyl)-1-methyl-2-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (106)    N-[3-(4-Methoxycarbonylphenyl)-1-methyl-2-phenylpropyl]-2-(4-Chlorophenyloxy)-2-methylpropanamide;-   (107)    N-[2-(2-Chlorophenyl)-1-methyl-3-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (108)    N-[2-(2-Chlorophenyl)-1-methyl-3-phenylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (109)    N-[2-(2-Chlorophenyl)-1-methyl-3-phenylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (110)    N-[2-(4-Methoxyphenyl)-1-methyl-3-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (111)    N-[2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-1-methyl-propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (112)    N-[2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-1-methyl-propyl]-2,2-dimethylpropanamide;-   (113)    N-[2-(4-Chlorophenyl)-2-(4-chloro-2-fluorophenyl)-1-methyl-propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (114)    N-[2-(4-Chlorophenyl)-2-(4-chloro-2-fluorophenyl)-1-methyl-propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (115)    N-[2-(4-Chlorophenyl)-2-(4-chloro-2-fluorophenyl)-1-methyl-propyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (116)    N-[3-(4-Chlorophenyl)-2-(4-fluorophenyl)-1-methyl-propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (117)    N-[3-(4-Chlorophenyl)-1-methyl-2-(2-pyridyl)propyl]-tert-butylcarbamate;-   (118)    N-[3-(4-Chlorophenyl)-1-methyl-2-(2-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (119)    N-[3-(4-Chlorophenyl)-1-methyl-2-(2-pyridyl)propyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (120)    N-[3-(4-Chlorophenyl)-1-methyl-2-(4-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (121)    N-[3-(4-Cyanophenyl)-1-methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (122)    N-[3-(5-Chloro-2-pyridyl)-1-methyl-2-phenylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (123)    N-[3-(4-Chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-tert-butylcarbamate;-   (124)    N-[3-(4-Chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (125)    N-[3-(4-Chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (126)    N-[3-(4-Chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(3-fluorophenyloxy)-2-methylpropanamide;-   (127)    N-[2-(4-Chlorophenoxy)-2-(4-chlorophenyl)ethyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (128) N-[2,2-Bis(4-chlorophenyl)ethyl]allylcarbamate;-   (129)    N-[2,2-Bis(4-chlorophenyl)ethyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (130)    N-[2-(4-Chlorophenylthio)-2-(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (131)    N-[2,3-Bis(4-Chlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (132)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-phenyloxy)-2-methylpropanamide;-   (133)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-phenyloxy-2-methylpropanamide;-   (134)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (135)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide;-   (136)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-fluorophenyloxy)-2-methylpropanamide;-   (137)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,4-difluorophenyloxy)-2-methylpropanamide;-   (138)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (139)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (140)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (141)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (142)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (143)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;-   (144)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;-   (145)    N-[3-(4-Chlorophenyl)-1-methyl-2-(2-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (146)    N-[3-(4-Cyanophenyl)-1-methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (147)    N-[3-(4-Chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (148)    N-[3-(4-Chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (149)    N-[3-(4-Chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(3-fluorophenyloxy)-2-methylpropanamide;-   (150)    N-[2-(4-Chlorophenoxy)-2-(4-chlorophenyl)ethyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (151)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (152)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(3,4,5-trifluorophenyloxy)-2-methylpropanamide;-   (153)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(3-chloro-4-fluorophenyloxy)-2-methylpropanamide;-   (154)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(4-chloro-3-fluorophenyloxy)-2-methylpropanamide;-   (155)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(3,4-dichlorophenyloxy)-2-methylpropanamide;-   (156)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(3,5-dichlorophenyloxy)-2-methylpropanamide;-   (157)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-3-hydroxy-2,2-dimethylpropanamide;-   (158)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-3-diethylamino-2,2-dimethylpropanamide;-   (159)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-3-cyclopropylamino-2,2-dimethylpropanamide;-   (160)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2,2-dimethyl-3-piperidinylpropanamide;-   (161)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-3-tert-butylamino-2,2-dimethylpropanamide;-   (162)    N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenylamino)-2-methylpropanamide;-   (163)    N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-pyridyloxy-N-oxide)-2-methylpropanamide;-   (164)    N-[3-(4-Chlorophenyl)-1-methyl-2-(3-pyridyl-N-oxide)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (165)    N-[3-(4-Chlorophenyl)-1-methyl-2-(3-pyridyl-N-oxide)propyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (166)    N-[3-(4-Chlorophenyl)-1(S)-methyl-2(S)-phenylpropyl]-2-(4-chloro-3,5-difluorophenyloxy)-2-methylpropanamide;-   (167)    N-[3(R)-(4-Chlorophenyl)-1(S),3-dimethyl-2(S)-phenylbutyl]-2-(3,5-difluoro-4-methylphenyloxy)-2-methylpropanamide;-   (168) N-[3    (S)-(4-Chlorophenyl)-1(S),3-dimethyl-2(S)-phenylbutyl]-2-(3,5-difluoro-4-methylphenyloxy)-2-methylpropanamide;-   (169)    N-[2,3-Bis(4-Chlorophenyl)-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide;-   (170)    N-[3-(4-Chlorophenyl)-2-phenyl-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide;-   (171)    N-(1,4-dimethyl-2-phenylpentyl)-2-(4-chlorophenoxy)-2-methylpropanamide;-   (172) N-(1-methyl-2-phenylpentyl)-2-(4-chlorophenoxy)-acetamide;-   (173) N-(1-methyl-2,5-diphenylpentyl)-2-(4-chlorophenoxy)-acetamide;-   (174)    N-(1,3-dimethyl-2-phenylbutyl)-2-(4-chlorophenoxy)-propanamide;-   (175)    N-(2,3-Diphenyl-1-methylpropyl)-2-(4-chlorophenoxy)-2-methylpropanamide;-   (176)    N-(2,3-Diphenyl-1-ethylpropyl)-2-(4-chlorophenoxy)-2-methylpropanamide;-   (177)    N-(3-(4-chlorophenyl)-2-phenyl-1-methylpropyl)-2-(4-chlorophenoxy)-acetamide;-   (178) N-(2,3-diphenyl-1-methylpropyl)-2-(4-chlorophenoxy)-acetamide;-   (179)    N-(3-(4-chlorophenyl)-2-phenyl-1-methylpropyl)-2-(4-chlorophenoxy)-propanamide;-   (180)    N-(2,3-diphenyl-1-methylpropyl)-2-(4-chlorophenoxy)-propanamide;-   (181)    N-(2,3-bis(4-chlorophenyl)-1-methylpropyl)-2-methyl-3-phenyl-propanamide;-   (182)    N-(2,3-bis(4-chlorophenyl)-1-methylpropyl)-2-methyl-3-(4-chlorophenyl)-propanamide;-   (183)    N-(3-(4-chlorophenyl)-2-phenyl-1-methylpropyl)-2-(4-chloro-anilino)-acetamide;-   (184)    N-(2,3-diphenyl-1-methylpropyl)-2-(4-chloro-anilino)-acetamide;-   (185)    N-(2,3-bis(4-chlorophenyl)-1-methylpropyl)-2,2-dimethyl-3-phenyl-propanamide;-   (186)    N-(3-(4-chlorophenyl)-2-phenyl-1-methylpropyl)-2-methyl-2-(4-chlorophenoxy)-propanamide;-   (187)    N-(3-(2-chlorophenyl)-2-phenyl-1-methylpropyl)-2-methyl-2-(4-chlorophenoxy)-propanamide;-   (188)    N-(3-(4-trifluoromethylphenyl)-2-phenyl-1-methylpropyl)-2-methyl-2-(4-chlorophenoxy)-propanamide;-   (189)    N-(3-(4-fluorophenyl)-2-phenyl-1-methylpropyl)-2-methyl-2-(4-chlorophenoxy)-propanamide;-   (190)    N-(3-(4-chlorophenyl)-2-phenyl-1-methylpropyl)-2-methyl-2-phenoxy-propanamide;-   (191)    N-(3-(4-chlorophenyl)-2-phenyl-1-methylpropyl)-2-methyl-2-(4-fluorophenoxy)-propanamide;-   (192)    N-(2,3-diphenyl-1-methylpropyl)-2-methyl-2-(4-fluorophenoxy)-propanamide;-   (193)    N-(3-phenyl-2-benzyl-1-methylpropyl)-2-methyl-2-(4-chlorophenoxy)-propanamide;-   (194)    N-[3-(4-Chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (195)    N-[3-(4-Chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-methyl-2-(3,4,5-trifluorophenyloxy)propanamide;-   (196)    N-[3-(4-Chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;-   (197)    N-[3-(4-Chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (198)    N-[3-(4-Chlorophenyl)-2-(3-pyridyl)-1l-methylpropyl]-2-(3,5-dichlorophenyloxy)-2-methylpropanamide;-   (199)    N-[3-(4-Chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (200)    N-[3-(4-Chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(3-chloro-5-fluorophenyloxy)-2-methylpropanamide;-   (201)    N-[3-(4-Chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;-   (202)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(3-chloro-5-fluorophenyloxy)-2-methylpropanamide;-   (203)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (204)    N-[3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (205)    N-[3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;-   (206)    N-[2-(3-Chlorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;-   (207)    N-[3-(4-Chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (208)    N-[3-(4-Chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-methyl-2-(3,4,5-trifluorophenyloxy)propanamide;-   (209)    N-[3-(4-Chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (210)    N-[3-(4-Chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;-   (211)    N-[3-(4-Chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(3,5-dichlorophenyloxy)-2-methylpropanamide;-   (212)    N-[3-(4-Chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (213)    N-[2-(3-Bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;-   (214)    N-[3-(4-chlorophenyl)-2-(3-iodophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;-   (215)    N-[2-(3-Bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;-   (216)    N-[3-(4-chlorophenyl)-2-(3-iodophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;-   (217)    N-[2-(3-Bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-methyl-2-(2-phenyloxy)propanamide;-   (218)    N-[3-(4-Chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;-   (219)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(3-chloro-5-fluorophenyloxy)-2-methylpropanamide;-   (220)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (221)    N-[3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (222)    N-[3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;-   (223)    N-[2-(3-Chlorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;-   (224)    N-[(2S,3S)-3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(5-chloropyridyloxy)-2-methylpropanamide;-   (225)    N-[(2S,3S)-3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(6-methylpyridyloxy)-2-methylpropanamide;-   (226)    N-[(2S,3S)-3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-chloro-5-fluorophenyloxy)-2-methylpropanamide;-   (227)    N-[(2S,3S)-3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-pyridazinyloxy)-2-methylpropanamide;-   (228)    N-[(2S,3S)-3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-trifluoromethylphenyloxy)-2-methylpropanamide;-   (229)    N-[(2S,3S)-3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(5-trifluoromethylpyridyloxy)-2-methylpropanamide;-   (230)    N-[(2S,3S)-3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4,6-dimethylpyridyloxy)-2-methylpropanamide;-   (231)    N-(3-(4-chlorophenyl)-2-cyclopentyl-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2-methylpropanamide;-   (232)    N-(3-(4-chlorophenyl)-2-cyclopentyl-1-methyl)propyl-2-(3,5-difluorophenoxy)-2-methylpropanamide;-   (233)    N-(3-(4-chlorophenyl)-2-ethoxy-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2-methylpropanamide;-   (234)    N-(3-(4-chlorophenyl)-2-isopropyl-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2-methylpropanamide;-   (235)    N-(3-(4-chlorophenyl)-1-methyl-2-propoxy)propyl-2-(3,5-dichlorophenoxy)-2-methylpropanamide;-   (236)    N-(3-(4-chlorophenyl)-1-methyl-2-pentoxy)propyl-2-(3,5-dichlorophenoxy)-2-methylpropanamide;-   (237)    N-(3-(4-chlorophenyl)-2-cyclopentylmethoxy-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2-methylpropanamide;-   (238)    N-(3-(4-chlorophenyl)-2-cyclobutylmethoxy-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2-methylpropanamide;-   (239)    N-(3-(4-chlorophenyl)-2-ethyl-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2-methylpropanamide;-   (240)    N-(3-(4-chlorophenyl)-2-methoxy-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2-methylpropanamide;-   (241)    N-(3-(4-chlorophenyl)-2-pyrrolidin-N-yl-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2-methylpropanamide;-   (242)    N-(3-(4-chlorophenyl)-2-benzyloxycarbonyl-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2-methylpropanamide;-   (243)    N-(2(1-(1,2,3-triazolyl))-3-(4-chlorophenyl)-1-methylpropyl)-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (244)    N-(2-(1-(1,2,4-triazolyl))-3-(4-chlorophenyl)-1-methylpropyl)-2-(2-pyridyloxy)-2-methylpropanamide;-   (245)    N-[3-(5-chloro-2-pyridyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;-   (246)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(3-trifluoromethylphenyloxy)-2-methylpropanamide;-   (247)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(6-chloro-2-pyridyloxy)-2-methylpropanamide;-   (248)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(4-cyanophenyloxy)-2-methylpropanamide;-   (249)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(3-cyanophenyloxy)-2-methylpropanamide;-   (250)    N-[3-(5-chloro-2-pyridyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (251)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(5-chloro-2-pyrimidyloxy)-2-methylpropanamide;-   (252)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(2-pyrimidyloxy)-2-methylpropanamide;-   (253)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (254)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide;-   (255)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(4-pyrimidyloxy)-2-methylpropanamide;-   (256) N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2    (R)-(4-trifluoromethyl-2-pyridyloxy)propanamide;-   (257)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(4-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (258)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;-   (259)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (260)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (261)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (262)    N-[2-(3-Bromo-5-fluorophenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (263)    N-[2-(3-Bromo-5-fluorophenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (264)    N-[2-(3-Chlorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;-   (265)    N-[2-(3-Chlorophenyl)-3-(5-chloro-2-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (266)    N-[2-(3-Chlorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (267)    N-[2-(3-Bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (268)    N-[2-(3-Bromophenyl)-3-(5-chloro-2-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (269)    N-[3-(4-Chlorophenyl)-2-(3-trifluoromethylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (270)    N-[3-(4-Chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (271)    N-[3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;-   (272)    N-[3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (273)    N-[3-(5-Chloro-2-pyridyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (274)    N-[3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (275)    N-[3-(4-Chlorophenyl)-2-(2-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (276)    N-[3-(4-Chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (277)    N-[3-(4-Chlorophenyl)-2-(5-fluoro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (278)    N-[3-(4-Chlorophenyl)-2-(5-fluoro-3-pyridyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (279)    N-[3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (280)    N-[3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide;-   (281)    N-[3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (282)    N-[3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyridyloxy)-2-methylpropanamide;-   (283)    N-[2-(5-Chloro-3-pyridyl)-3-cyclobutyl-1-methylpropyl]-2-(6-trifluoromethyl-4-pyridyloxy)-2-methylpropanamide;-   (284)    N-[2-(5-Chloro-3-pyridyl)-3-cyclobutyl-5-methyl-2-hexyl]-2-(6-trifluoromethyl-4-pyridyloxy)-2-methylpropanamide;-   (285)    N-[3-(4-Chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (286)    N-[3-(4-Chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (287)    N-[3-(4-Chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (288)    N-[2-(5-Bromo-3-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (289)    N-[2-(5-Bromo-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (290)    N-[2-(5-Bromo-3-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (291)    N-[2-(5-Bromo-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (292)    N-[2-(5-Bromo-3-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (293)    N-[3-(4-Chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (294)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;-   (295)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;-   (296)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (297)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (298)    N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (299)    N-[2-(3-Chlorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;-   (300)    N-[2-(3-Chlorophenyl)-3-(5-chloro-2-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (301)    N-[2-(3-Chlorophenyl)-3-(4-chlorophenyl)-1-methylpropyl-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (302)    N-[2-(3-Bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;-   (303)    N-[2-(3-Bromophenyl)-3-(5-chloro-2-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (304)    N-[3-(4-chlorophenyl)-2-(3-trifluoromethylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (305)    N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (306)    N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;-   (307)    N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl    -2-pyridyloxy)-2-methylpropanamide;-   (308)    N-[3-(4-Chlorophenyl)-2-(2-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (309)    N-[3-(4-Chlorophenyl)-2-(5-fluoro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (310)    N-[3-(4-Chlorophenyl)-2-(5-fluoro-3-pyridyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (311)    N-[3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (312)    N-[3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (313)    N-[3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide;-   (314)    N-[3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (315)    N-[2-(5-chloro-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-4-pyridyloxy)-2-methylpropanamide;-   (316)    N-[2-(5-chloro-3-pyridyl)-3-cyclobutyl-1-methylpropyl]-2-(5-trifluoromethyl-4-pyridyloxy)-2-methylpropanamide;-   (317)    N-[2-(5-chloro-3-pyridyl)-3-cyclobutyl-1-methylpropyl]-2-(5-trifluoromethyl-4-pyridyloxy)-2-methylpropanamide;-   (318)    N-[2-(5-chloro-3-pyridyl)-1,4-dimethylpentyl]-2-(5-trifluoromethyl-4-pyridyloxy)-2-methylpropanamide;-   (319)    N-[2-(5-chloro-3-pyridyl)-1,4-dimethylpentyl]-2-(5-trifluoromethyl-4-pyridyloxy)-2-methylpropanamide;-   (320)    N-[3-(4-Chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (321)    N-[3-(4-Chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (322)    N-[2-(5-cyano-3-pyridyl)-3-(3,4-difluorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (323)    N-[3-(3-Chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (324)    N-[2-(5-cyano-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (325)    N-[2-(5-Bromo-3-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (326)    N-[2-(5-Bromo-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (327)    N-[2-(5-Bromo-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (328)    N-[2-(5-Bromo-3-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (329)    N-[3-(4-Chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (330)    N-[2-(3-Bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;-   (331)    N-[3-(4-Chlorophenyl)-2-(3-cyano-5-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (332)    N-[2-(3-Cyano-5-fluorophenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (333)    N-[2-(3-Cyano-5-fluorophenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (334)    N-[3-(4-Chlorophenyl)-2-(3-cyano-5-fluorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (335)    N-[3-(5-Chloro-2-pyridyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (336)    N-[2-(5-Chloro-3-pyridyl)-3-(4-chloro-3-iodophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (337)    N-[3-(4-Chloro-3-iodophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (338)    N-(3-(4-chlorophenyl)-2-benzisoxazol-3-yl)-1-methyl)propyl-2-(5-chloro-2-oxypyridine-2-yl)-2-methylpropanamide;-   (339)    N-(3-(4-chlorophenyl)-2-(benzisoxazol-3-yl)-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2-methylpropanamide;-   (340)    N-(3-(4-chlorophenyl)-2-(benzisoxazol-3-yl)-1-methyl)propyl-2-(5-trifluoromethyl-2-oxypyridine-2-yl)-2-methylpropanamide;-   (341)    N-(3-(4-chlorophenyl)-2-(7-azaindol-N-yl)-1-methyl)propyl-2-(5-trifluoromethyl-2-oxypyridine-2-yl)-2-methylpropanamide;-   (342)    N-(3-(4-chlorophenyl)-2-(N-methyl-N-phenyl)amino-1-methyl)propyl-2-(5-trifluoromethyl-2-oxypyridine-2-yl)-2-methylpropanamide;-   (343)    N-(3-(4-chlorophenyl)-2-(indol-N-yl)-1-methyl)propyl-2-(5-trifluoromethyl-2-oxypyridine-2-yl)-2-methylpropanamide;-   (344)    N-(3-(4-chlorophenyl)-2-(indolin-N-yl)-1-methyl)propyl-2(4-trifluoromethyl-2-oxypyridine-2-yl)-2-methylpropanamide;-   (345)    N-(3-(4-chlorophenyl)-2-(indolin-N-yl)-1-methyl)propyl-2(5-trifluoromethyl-2-oxypyridine-2-yl)-2-methylpropanamide;-   (346)    2-Methyl-N-[1-methyl-3-(4-methylphenyl)-2-phenylpropyl]-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide;-   (347)    N-[3-(4-Methoxyphenyl)-1-methyl-2-phenylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide;-   (348)    N-[3-(4-Fluorophenyl)-1-methyl-2-phenylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy    }propanamide;-   (349)    N-[3-(4-Cyanophenyl)-1-methyl-2-phenylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide;-   (350)    N-[2-(3-Cyanophenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide;-   (351)    N-(2-(1H-1,2,3-Benzotriazol-1-yl)-3-(4-chlorophenyl)-1-methylpropyl)-2-methyl-2-(5-chloropyridin-2-yl)oxy)-2-methylpropanamide;-   (352)    N-(2-(1H-1,2,3-Benzotriazol-1-yl)-3-(4-chlorophenyl)-1-methylpropyl)-2-methyl-2-(5-trifluoromethylpyridin-2-yl)oxy)-2-methylpropanamide;-   (353)    N-(2-(1H-1,2,3-Benzotriazol-1-yl)-3-(4-chlorophenyl)-1-methylpropyl)-2-methyl-2-(4-chlorophenoxy)-2-methylpropanamide;-   (354)    N-(3-(4-chlorophenyl)-1-methyl-2-(1H-indazol-1-yl)propyl)-2-methyl-2-(5-trifluoromethylpyridin-2-yl)oxy)-2-methylpropanamide;-   (355)    N-(3-(4-chlorophenyl)-1-methyl-2-(1-methyl-1H-indol-3-yl)propyl)-2-methyl-2-(5-chloropyridin-2-yl)oxy)-2-methylpropanamide;-   (356)    N-(3-(4-chlorophenyl)-1-methyl-2-(1-methyl-1H-indol-3-yl)propyl)-2-methyl-2-(5-trifluoromethylpyridin-2-yl)oxy)-2-methylpropanamide;-   (357)    N-(3-(4-chlorophenyl)-1-methyl-2-(1-methyl-1H-indol-3-yl)propyl)-2-methyl-2-(4-chlorophenoxy)-2-methylpropanamide;-   (358)    N-(3-(4-chlorophenyl)-1-methyl-2-(1-methyl-1H-indol-4-yl)propyl)-2-methyl-2-(5-trifluoromethylpyridin-2-yl)oxy)-2-methylpropanamide;-   (359)    N-(3-(4-chlorophenyl)-1-methyl-2-(thiophen-2-yl)propyl)-2-methyl-2-(5-chloropyridin-2-yl)oxy)-2-methylprpoanamide;-   (360)    N-(3-(4-chlorophenyl)-1-methyl-2-(thiophen-3-yl)propyl)-2-methyl-2-(5-chloropyridin-2-yl)oxy)-2-methylprpoanamide;-   (361)    N-(3-(4-chlorophenyl)-1-methyl-2-(pyrimidin-5-yl)propyl)-2-methyl-2-(5-chloropyridin-2-yl)oxy)-2-methylprpoanamide;-   (362)    N-(3-(4-chlorophenyl)-1-methyl-2-(pyradizin-3-yl)propyl)-2-methyl-2-(5-chloropyridin-2-yl)oxy)-2-methylprpoanamide;-   (363)    N-(2-(3-cyanophenyl)-3-cyclopropyl-1-methylpropyl)-2-methyl-2((5-(trifluoromethyl)pyridin-2-yl)oxy)-propanamide;-   (364)    N-(2-(3-cyanophenyl)-1,4-dimethylpentyl)-2-methyl-2((5-(trifluoromethyl)pyridin-2-yl)oxy)-propanamide;-   (365)    N-(2-(3-cyanophenyl)-3-cyclobutyl-1-methylpropyl)-2-methyl-2((5-(trifluoromethyl)pyridin-2-yl)oxy)-propanamide;-   (366)    N-(2-(3-cyanophenyl)-3-cyclohexyl-1-methylpropyl)-2-methyl-2((5-(trifluoromethyl)pyridin-2-yl)oxy)-propanamide;-   (367)    N-(2-(3-cyanophenyl)-3-cyclopentyl-1-methylpropyl)-2-methyl-2((5-(trifluoromethyl)pyridin-2-yl)oxy)-propanamide;-   (368)    N-(2-(3-cyanophenyl)-3-((1-tertbutyloxycarbonyl)piperidin-4-yl)-1-methylpropyl)-2-methyl-2((5-(trifluoromethyl)pyridin-2-yl)oxy)-propanamide;-   (369)    N-(2-(2,3-Dihydro-1H-indol-1-yl)-1,4-dimethylpentyl)-2-methyl-2((5-(trifluoromethyl)pyridin-2-yl)oxy)-propanamide;-   (370)    N-(3-Cyclobutyl-2-(3,4-dihydroquinolin-1(2H)-yl)-1-methylpropyl)-2-methyl-2((5-(trifluoromethyl)pyridin-2-yl)oxy)-propanamide;-   (371)    N-(2-(3,4-dihydroquinolin-1(2H)-yl)-1,4-dimethylpentyl)-2-methyl-2((5-(trifluoromethyl)pyridin-2-yl)oxy)-propanamide;-   (372)    N-(2-(3-cyanophenyl)-1,4-dimethylpentyl)-2-methyl-2((5-(trifluoromethyl)pyridin-2-yl)oxy)-propanamide;-   (373)    N-(2-(3-cyanophenyl)-3-cyclobutyl-1-methylpropyl)-2-methyl-2((5-(trifluoromethyl)pyridin-2-yl)oxy)-propanamide;-   (374)    N-(2-(3-cyanophenyl)-3-cyclopentyl-1-methylpropyl)-2-methyl-2((5-(trifluoromethyl)pyridin-2-yl)oxy)-propanamide;-   (375)    N-(2-(3-cyanophenyl)-3-cyclohexyl-1-methylpropyl)-2-methyl-2((5-(trifluoromethyl)pyridin-2-yl)oxy)-propanamide;-   (376)    N-[3-(4-chlorophenyl)-2-(3-methylthiophenyl)-1-methylpropyl]-2-methyl-2-(5-trifluoromethylpyridin-2-oxy)propanamide;-   (377)    N-[3-(4-chlorophenyl)-2-(3-methylsulfonylphenyl)-1-methylpropyl]-2-methyl-2-(5-trifluoromethylpyridin-2-oxy)propanamide;-   (378)    N-[3-(4-chlorophenyl)-2-(3-methylsulfonylphenyl)-1-methylpropyl]-2-methyl-2-(5-trifluoromethylpyridin-2-oxy)propanamide;-   (379)    N-[3-(4-chlorophenyl)-2-(3-methylsulfonylphenyl)-1-methylpropyl]-2-methyl-2-(5-trifluoromethylpyridin-2-oxy)propanamide;-   (380)    N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-(5-methylsulfonylpyridin-2-oxy)propanamide;-   (381)    N-[3-(4-chlorophenyl)-2-(3-methylthiophenyl)-1-methylpropyl]-2-methyl-2-(5-trifluoromethylpyridin-2-oxy)propanamide;-   (382)    N-[3-(4-chlorophenyl)-2-(3-methylthiophenyl)-1-methylpropyl]-2-methyl-2-(5-trifluoromethylpyridin-2-oxy)propanamide;    and pharmaceutically acceptable salts thereof.

In one particular subclass of compounds of the present invention, R¹ isselected from:

-   -   (1) ethyl,    -   (2) isopropyl,    -   (3) isobutyl,    -   (4) n-propyl,    -   (5) n-pentyl,    -   (6) cyclopentyl,    -   (7) pyrrolidinyl,    -   (8) phenyl,    -   (9) phenyl-C₁₋₄alkyl,    -   (10) pyridyl,    -   (11) pyridyl-C₁₋₄alkyl,    -   (12) triazolyl,    -   (13) ethyloxy,    -   (14) propyloxy,    -   (15) butyloxy,    -   (16) n-pentyloxy,    -   (17) benzyloxylcarbonyl,    -   (18) cyclopentylmethyloxy,    -   (19) cyclobutylmethyloxy,        wherein each phenyl is optionally substituted with one or two        substituents selected from halogen, and methoxy, and each        pyridyl is optionally present as the N-oxide;

R² is selected from:

-   -   (1) isopropyl,    -   (2) isobutyl,    -   (3) n-propyl,    -   (4) phenyl,    -   (5) benzyl,    -   (6) phenylethyl,    -   (7) 3-phenylpropyl,    -   (8) 2-phenylpropyl,    -   (9) phenoxy,    -   (10) phenylthio,        wherein each aryl and heteroaryl is optionally substituted with        one or two substituents selected from halogen, trifluoromethyl,        cyano, methoxycarbonyl, and methoxy;

R³ is selected from:

-   -   (1) hydrogen,    -   (2) methyl, and    -   (3) ethyl;

R⁴ is hydrogen;

R⁵ is C₁₋₈alkyl substituted with —OR^(d);

R^(d) is selected from:

-   -   (1) hydrogen,    -   (2) C₁₋₄alkyl,    -   (3) C₂₋₆alkenyl,    -   (4) cycloalkyl,    -   (5) cycloalkyl-C₁₋₄alkyl;    -   (6) cycloheteroalkyl,    -   (7) cycloheteroalkyl-C₁₋₄ alkyl;    -   (8) phenyl,    -   (9) heteroaryl,    -   (10) phenyl-C₁₋₄alkyl, and    -   (11) heteroaryl-C₁₋₄alkyl,        wherein each R^(d) may be unsubstituted or substituted with one        to three substituents selected from R^(h);        each R^(h) is independently selected from:    -   (1) halogen,    -   (2) C₁₋₄alkyl,    -   (3) —O—C₁₋₄alkyl,    -   (4) —S—C₁₋₄alkyl,    -   (5) —CN,    -   (6) —CF₃, and    -   (7) —OCF₃;        and pharmaceutically acceptable salts thereof.

Particular compounds of this subclass include:

-   (1)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (2)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-cyclohexyloxy)-2-methylpropanamide;-   (3)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-cyclohexyloxy)-2-methylpropanamide;-   (4)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(2-fluorophenyloxy)-2-methylpropanamide;-   (5)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(3-fluorophenyloxy)-2-methylpropanamide;-   (6)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(3,4-difluorophenyloxy)-2-methylpropanamide;-   (7)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (8)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(2-chlorophenyloxy)-2-methylpropanamide;-   (9)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (10)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(3-cyanophenyloxy)-2-methylpropanamide;-   (11)    N-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (12)    N-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (13)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-phenyloxy-2-methylpropanamide;-   (14)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (15)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(3-pyridyloxy)-2-methylpropanamide;-   (16)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(2-pyridylox)-2-methylbutanamide;-   (17)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;-   (18)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-pyridyloxy)-2-methylpropanamide;-   (19)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-fluorophenyloxy)-2-methylpropanamide;-   (20)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-fluorophenyloxy)-2-methylpropanamide;-   (21)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,4-difluorophenyloxy)-2-methylpropanamide;-   (22)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (23)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-chlorophenyloxy)-2-methylpropanamide;-   (24)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (25)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-cyclohexyloxy-2-methylpropanamide;-   (26)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (27)    N-[3-(4-chlorophenyl)-2-(2-fluorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (28)    N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (29)    N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (30)    N-[3-(4-chlorophenyl)-2-(2-fluorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (31)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl)]-2-methyl-2-phenylpropanamide;-   (32)    N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;-   (33)    N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (34)    N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (35)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-pyridyloxy)-2-methylpropanamide;-   (36)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylbutanamide;-   (37)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;-   (38)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-pyridyloxy)-2-methylpropanamide;-   (39)    N-[2-(4-chlorophenyl)-1-methyl-3-phenylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (40)    N-[2-(4-chlorophenyl)-1-methyl-3-phenylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (41)    N-[2-(4-chlorophenyl)-1-methyl-3-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (42)    N-[2-(4-chlorophenyl)-1-methyl-3-phenylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (43)    N-[3-(4-methoxycarbonylphenyl)-1-methyl-2-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (44)    N-[3-(4-methoxycarbonylphenyl)-1-methyl-2-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (45)    N-[3-(4-methoxycarbonylphenyl)-1-methyl-2-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (46)    N-[3-(4-methoxycarbonylphenyl)-1-methyl-2-phenylpropyl]-2-(4-Chlorophenyloxy)-2-methylpropanamide;-   (47)    N-[2-(2-chlorophenyl)-1-methyl-3-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (48)    N-[2-(2-chlorophenyl)-1-methyl-3-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (49)    N-[2-(2-chlorophenyl)-1-methyl-3-phenylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (50)    N-[2-(2-chlorophenyl)-1-methyl-3-phenylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (51)    N-[2-(4-methoxyphenyl)-1-methyl-3-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (52)    N-[2-(4-methoxyphenyl)-1-methyl-3-phenylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (53)    N-[2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-1-methyl-propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (54)    N-[2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-1-methyl-propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (55)    N-[2-(4-chlorophenyl)-2-(4-chloro-2-fluorophenyl)-1-methyl-propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (56) N-[2-(4-chlorophenyl)-2-(4-chloro    2-fluorophenyl)-1-methyl-propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (57)    N-[2-(4-chlorophenyl)-2-(4-chloro-2-fluorophenyl)-1-methyl-propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (58)    N-[2-(4-chlorophenyl)-2-(4-chloro-2-fluorophenyl)-1-methyl-propyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (59)    N-[2-(4-chlorophenyl)-2-(4-chloro-2-fluorophenyl)-1-methyl-propyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (60)    N-[3-(4-chlorophenyl)-2-(4-fluorophenyl)-1-methyl-propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (61)    N-[3-(4-chlorophenyl)-2-(4-fluorophenyl)-1-methyl-propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (62)    N-[3-(4-chlorophenyl)-1-methyl-2-(2-pyridyl)propyl]-tert-butylcarbamate;-   (63)    N-[3-(4-chlorophenyl)-1-methyl-2-(2-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (64)    N-[3-(4-chlorophenyl)-1-methyl-2-(2-pyridyl)propyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (65)    N-[3-(4-chlorophenyl)-1-methyl-2-(4-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (66)    N-[3-(4-cyanophenyl)-1-methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (67)    N-[3-(5-chloro-2-pyridyl)-1-methyl-2-phenylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (68)    N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-tert-butylcarbamate;-   (69)    N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (70)    N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (71)    N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(3-fluorophenyloxy)-2-methylpropanamide;-   (72)    N-[2-(4-chlorophenoxy)-2-(4-chlorophenyl)ethyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (73)    N-[2,2-bis(4-chlorophenyl)ethyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (74)    N-[2-(4-chlorophenylthio)-2-(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (75)    N-[2-(4-chlorophenylthio)-2-(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (76)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (77)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-phenyloxy)-2-methylpropanamide;-   (78)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-phenyloxy-2-methylpropanamide;-   (79)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (80)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (81)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide;-   (82)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide;-   (83)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-fluorophenyloxy)-2-methylpropanamide;-   (84)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-fluorophenyloxy)-2-methylpropanamide;-   (85)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,4-difluorophenyloxy)-2-methylpropanamide;-   (86)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,4-difluorophenyloxy)-2-methylpropanamide;-   (87)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (88)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (89)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (90)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (91)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (92)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (93)    N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (94)    N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(4-fluorophenyloxy)-2-methylpropanamide;-   (95)    N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (96)    N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (97)    N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;-   (98)    N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;-   (99)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide-   (100)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;-   (101)    N-[3-(4-chlorophenyl)-1-methyl-2-(2-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (102)    N-[3-(4-chlorophenyl)-1-methyl-2-(2-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (103)    N-[3-(4-cyanophenyl)-1-methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (104)    N-[3-(4-cyanophenyl)-1-methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (105)    N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (106)    N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (107)    N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (108)    N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (109)    N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(3-fluorophenyloxy)-2-methylpropanamide;-   (110)    N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(3-fluorophenyloxy)-2-methylpropanamide;-   (111)    N-[2-(4-chlorophenoxy)-2-(4-chlorophenyl)ethyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (112)    N-[2-(4-chlorophenoxy)-2-(4-chlorophenyl)ethyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (113)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (114)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(3,4,5-trifluorophenyloxy)-2-methylpropanamide;-   (115)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(3-chloro-4    -fluorophenyloxy2-methylpropanamide;-   (116)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(4-chloro-3-fluorophenyloxy-2-methylpropanamide;-   (117)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(3,4-dichlorophenyloxy)-2-methylpropanamide;-   (118)    N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(3,5-dichlorophenyloxy)-2-methylpropanamide;-   (119)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-pyridyloxy-N-oxide)-2-methylpropanamide;-   (120)    N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl-N-oxide)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (121)    N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl-N-oxide)propyl]-2-(3,5-difluorophenyl-2-methylpropanamide;-   (122)    N-[3-(4-chlorophenyl)-1(S)-methyl-2(S)-phenylpropyl]-2-(4-chloro-3,5-difluorophenyloxy)-2-methylpropanamide;-   (123)    N-[3(R,S)-(4-chlorophenyl)-1(S),3-dimethyl-2(S)-phenylbutyl]-2-(3,5-difluoro-4-methylphenyloxy)-2-methylpropanamide;-   (124)    N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide;-   (125)    N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide;-   (126)    N-(1,4-dimethyl-2-phenylpentyl)-2-(4-chlorophenoxy)-2-methylpropanamide;-   (127)    N-(2,3-diphenyl-1-methylpropyl)-2-(4-chlorophenoxy)-2-methylpropanamide;-   (128)    N-(2,3-diphenyl-1-ethylpropyl)-2-(4-chlorophenoxy)-2-methylpropanamide;-   (129)    N-(3-(4-chlorophenyl)-2-phenyl-1-methylpropyl)-2-methyl-2-(4-chlorophenoxy)-propanamide;-   (130)    N-(3-(2-chlorophenyl)-2-phenyl-1-methylpropyl)-2-methyl-2-(4-chlorophenoxy)-propanamide;-   (131)    N-(3-(4-trifluoromethylphenyl)-2-phenyl-1-methylpropyl)-2-methyl-2-(4-chlorophenoxy)-propanamide;-   (132)    N-(3-(4-fluorophenyl)-2-phenyl-1-methylpropyl)-2-methyl-2-(4-chlorophenoxy)-propanamide;-   (133)    N-(3-(4-chlorophenyl)-2-phenyl-1-methylpropyl)-2-methyl-2-phenoxy-propanamide;-   (134)    N-(3-(4-chlorophenyl)-2-phenyl-1-methylpropyl)-2-methyl-2-(4-fluorophenoxy)-propanamide;-   (135)    N-(2,3-diphenyl-1-methylpropyl)-2-methyl-2-(4-fluorophenoxy)-propanamide;    and-   (136)    N-(3-phenyl-2-benzyl-1-methylpropyl)-2-methyl-2-(4-chlorophenoxy)-propanamide;    and pharmaceutically acceptable salts thereof.

In another embodiment of the present invention,

-   R¹ is selected from:    -   (1) cycloheteroalkyl,    -   (2) aryl,    -   (3) heteroaryl, and    -   (4) —NR^(c)R^(d);    -   wherein aryl and heteroaryl are optionally substituted with one        to three substituents independently selected from R^(b);-   R² is selected from:    -   (1) C₁₋₁₀alkyl,    -   (2) C₃₋₁₀cycloalkyl-C₁₋₄alkyl,    -   (3) aryl-C₁₋₄alkyl,    -   (4) heteroaryl-C₁₋₄alkyl,    -   wherein each cycloalkyl, aryl and heteroaryl is optionally        substituted with one to three substituents independently        selected from R^(b);-   R³ is methyl;-   R⁴ is hydrogen;-   R⁵ is-   each R^(b) is independently selected from:    -   (1) halogen,    -   (2) cyano,    -   (3) trifluoromethyl,    -   (4) trifluoromethoxy,    -   (5) C₁₋₃alkyloxy, and    -   (6) C₁₋₃alkyl;-   each R^(c) is independently selected from:    -   (1) hydrogen,    -   (2) methyl, and    -   (3) trifluoromethyl;-   R^(d) is independently selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) cycloalkyl,    -   (4) aryl,    -   (5) heteroaryl,    -   (6) arylmethyl, and    -   (7) heteroarylmethyl,-   each R^(d) may be unsubstituted or substituted with one to three    substituents selected from R^(h);

each R^(h) is independently selected from:

-   -   (1) halogen,    -   (2) C₁₋₃alkyl,    -   (3) —CN, and    -   (4) —CF₃;        wherein when pyridyl groups are present in the molecule        unsubstituted on the nitrogen, they are may optionally be        present as the N-oxide; and pharmaceutically acceptable salts        thereof.

In one class of this embodiment, R¹ is selected from:

-   -   (1) phenyl,    -   (2) pyridyl,    -   (3) indolyl,    -   (4) 7-aza-indolyl,    -   (5) thiophenyl, and    -   (6)        wherein each aryl and heteroaryl is optionally substituted with        one or two substitutents independently selected from R^(b), and        each pyridyl is optionally present as the N-oxide.

In one subclass of this class of the present invention, R¹ is selectedfrom:

-   -   (1) phenyl,    -   (2) 3-cyanophenyl,    -   (3) 3-methylphenyl,    -   (4) 3,5-difluorophenyl,    -   (5) 3-pyridyl,    -   (6) 5-chloro-3-pyridyl,    -   (7) 5-methyl-3-pyridyl,    -   (8) 5-cyano-3-pyridyl,    -   (9) 1-oxido-5-cyano-3-pyridyl,    -   (10) 1-indolyl,    -   (11) 7-aza-indol-N-yl,    -   (12) 2-thiophenyl, and    -   (13)

In another subclass of this class of the present invention, R¹ is5-cyano-3-pyridyl.

In another class of this embodiment, R² is selected from:

-   -   (1) C₁₋₆alkyl,    -   (2) C₃₋₆cycloalkylmethyl,    -   (3) phenylmethyl,    -   (4) heteroarylmethyl,        wherein each cycloalkyl, aryl and heteroaryl is optionally        substituted with one to three substituents independently        selected from R^(b).

In one subclass of this class of the present invention, R² is selectedfrom:

-   -   (1) C₁₋₆alkyl,    -   (2) C₄₋₆cycloalkylmethyl,    -   (3) phenylmethyl,    -   (4) pyridyl,    -   wherein each cycloalkyl, aryl and heteroaryl is optionally        substituted with one or two substituents independently selected        from R^(b).

In another subclass of this class of the present invention, R² isselected from:

-   -   (1) 2-methylpropyl,    -   (2) n-pentyl,    -   (3) cyclobutylmethyl,    -   (4) cyclopentylmethyl,    -   (5) cyclohexylmethyl,    -   (6) benzyl,    -   (7) 4-chlorobenzyl,    -   (8) 4-methylbenzyl,    -   (9) 4-fluorobenzyl,    -   (10) 4-methoxybenzyl, and    -   (11) (5-chloro-2-pyridyl)methyl.

In one class of this embodiment, each R^(b) is independently selectedfrom:

-   -   (1) halogen,    -   (2) cyano,    -   (3) C₁₋₃alkyloxy and    -   (4) C₁₋₃alkyl.

In one subclass of this class, each R^(b) is independently selectedfrom:

-   -   (1) fluoro,    -   (2) chloro,    -   (3) bromo,    -   (4) iodo,    -   (5) cyano,    -   (6) methoxy, and    -   (7) methyl.

In another subclass of this class, each R^(b) is independently selectedfrom:

-   -   (1) fluoro,    -   (2) chloro,    -   (3) cyano,    -   (4) methoxy, and    -   (5) methyl.

In one class of this embodiment, each R^(c) is independently selectedfrom:

-   -   (1) hydrogen,    -   (2) methyl, and    -   (3) trifluoromethyl.

In one subclass, R^(c) is methyl.

In one class of this embodiment, R^(d) is selected from:

-   -   (1) C₄₋₆cycloalkyl,    -   (2) aryl, and    -   (3) heteroaryl,        wherein R^(d) may be unsubstituted or substituted with one or        two substituents selected from R^(h).

In one subclass of the present invention, R^(d) is selected from:

-   -   (1) phenyl,    -   (2) pyridyl, and    -   (3) pyrimidinyl,        wherein R^(d) may be unsubstituted or substituted with one or        two substituents selected from R^(h).

In another subclass of the present invention, R^(d) is selected from:

-   -   (1) phenyl,    -   (2) 4-chlorophenyl,    -   (3) 3-chlorophenyl,    -   (4) 3,5-difluorophenyl,    -   (5) 3,5-dichlorophenyl,    -   (6) 2-pyridyl,    -   (7) 5-chloro-2-pyridyl,    -   (8) 6-methyl-2-pyridyl,    -   (9) 5-trifluoromethyl-2-pyridyl,    -   (10) 4-trifluoromethyl-2-pyridyl,    -   (11) 4-trifluoromethyl-2-pyrimidyl, and    -   (12) 6-trifluoromethyl-4-pyrimidyl.    -   In yet another subclass of the present invention, R^(d) is        5-trifluoromethyl-2-pyridyl.

In one class of this embodiment, each R^(h) is independently selectedfrom:

-   -   (1) halogen,    -   (2) C₁₋₃alkyl,    -   (3) —CN, and    -   (4) —CF₃.

In one subclass of this class, each R^(h) is independently selectedfrom:

-   -   (1) fluoro,    -   (2) chloro,    -   (3) methyl,    -   (4) —CN, and    -   (5) —CF₃.

Particular novel compounds of this embodiment which may be employed inthe methods, uses and compositions of the present invention, include:

-   (1)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (2)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide-   (3)    N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;-   (4)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;-   (5)    N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(3,5-dichlorophenyloxy)-2-methylpropanamide;-   (6)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;-   (7)    N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;-   (8)    N-[3-(4-chlorophenyl)-1-methyl-2-phenyl-propyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;-   (9)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(6-methyl-pyridyloxy)-2-methylpropanamide;-   (10)    N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(phenyloxy)-2-methylpropanamide;-   (11)    N-[(3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(5-trifluoromethylpyridyloxy)-2-methylpropanamide;-   (12)    N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (13)    N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (14)    N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (15)    N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromrthyl-2-pyridyloxy)-2-methylpropanamide;-   (16)    N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (17)    N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide;-   (18)    N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (19)    N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy-2-methylpropanamide;-   (20)    N-[3-(4-chlorophenyl)-1-methyl-2-(thiophen-3-yl)propyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;-   (21)    N-[3-(5-chloro-2-pyridyl)-2-phenyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (22)    N-[3-(4-methyl-phenyl)-1-methyl-2-phenylpropyl]-2-(4-trifluoromethyl-phenyloxy)-2-methylpropanamide;-   (23)    N-[3-(4-fluoro-phenyl)-2-(3-cyano-phenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (24)    N-[3-(4-chlorophenyl)-2-(1-indolyl)-1-methyl)propyl]-2-(5-trifluoromethyl-2-oxypyridine-2-yl)-2-methylpropanamide;-   (25)    N-[3-(4-chlorophenyl)-2-(7-azaindol-N-yl)-1-methyl)propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (26)    N-[3-(4-chloro-phenyl)-2-(1-indolinyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (27)    N-[3-(4-chloro-phenyl)-2-(N-methyl-anilino)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (28)    N-[3-(4-methoxy-phenyl)-2-(3-cyano-phenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (29)    N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   (30)    N-[2-(3-cyanophenyl)-1,4-dimethylpentyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (31)    N-[3-(4-chlorophenyl)-2-(1-oxido-5-cyano-3-pyridyl]-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (32)    N-[2-(3-cyanophenyl)-3-cyclobutyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (33)    N-[2-(3-cyanophenyl)-1-methyl-heptyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (34)    N-[2-(3-cyanophenyl)-3-cyclopentyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   (35)    N-[2-(3-cyanophenyl)-3-cyclohexyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;    and pharmaceutically acceptable salts thereof.

The present invention is also directed to a compound of strucutralformula I, wherein:

-   R¹ is selected from:    -   (1) phenyl,    -   (2) pyridyl,    -   (3) indolyl,    -   (4) 7-aza-indolyl,    -   (5) thiophenyl, and    -   (6)    -   wherein each aryl and heteroaryl is optionally substituted with        one or two substitutents independently selected from R^(b), and        each pyridyl may be optionally present as the N-oxide;-   R² is selected from:    -   (1) C₁₋₆alkyl,    -   (2) C₃₋₆cycloalkylmethyl,    -   (3) phenylmethyl,    -   (4) heteroarylmethyl,        wherein each cycloalkyl, aryl and heteroaryl is optionally        substituted with one to three substituents independently        selected from R^(b);-   each R^(b) is independently selected from:    -   (1) halogen,    -   (2) cyano,    -   (3) C₁₋₃alkyloxy and    -   (4) C₁₋₃alkyl;-   R^(d) is selected from:    -   (1) phenyl,    -   (2) pyridyl, and    -   (3) pyrimidinyl,        wherein R^(d) may be unsubstituted or substituted with one or        two substituents selected from R^(h);-   each R^(h) is independently selected from:    -   (1) fluoro,    -   (2) chloro,    -   (3) methyl,    -   (4) —CN, and    -   (5) —CF₃;        and pharmaceutically acceptable salts thereof.

“Alkyl”, as well as other groups having the prefix “alk”, such asalkoxy, alkanoyl, means carbon chains which may be linear or branched orcombinations thereof. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl,octyl, nonyl, and the like.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched or combinationsthereof. Examples of alkenyl include vinyl, allyl, isopropenyl,pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl,and the like.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched or combinationsthereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkyl” means mono- or bicyclic or bridged saturated carbocyclicrings, each of which having from 3 to 10 carbon atoms. The term alsoincludes monocyclic rings fused to an aryl group in which the point ofattachment is on the non-aromatic portion. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.

“Aryl” means mono- or bicyclic aromatic rings containing only carbonatoms. The term also includes aryl group fused to a monocycliccycloalkyl or monocyclic cycloheteroalkyl group in which the point ofattachment is on the aromatic portion. Examples of aryl include phenyl,naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl,dihydrobenzopyranyl, 1,4-benzodioxanyl, and the like.

“Heteroaryl” means a mono- or bicyclic aromatic ring containing at leastone heteroatom selected from N, O and S, with each ring containing 5 to6 atoms. Examples of heteroaryl include pyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl,thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl,thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl,furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, imidazothiazolyl,and the like. The heteroaryl ring may be substituted on one or morecarbon or nitrogen atoms

“Cycloheteroalkyl” means mono- or bicyclic or bridged saturated ringscontaining at least one heteroatom selected from N, S and O, each ofsaid ring having from 3 to 10 atoms in which the point of attachment maybe carbon or nitrogen. The term also includes monocyclic heterocyclefused to an aryl or heteroaryl group in which the point of attachment ison the non-aromatic portion. Examples of “cycloheteroalkyl” includepyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl,2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, benzoxazolinyl,2-H-phthalazinyl, isoindolinyl, benzoxazepinyl,5,6-dihydroimidazo[2,1-b]thiazolyl, tetrahydrohydroquinolinyl,morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like. Theterm also includes partially unsaturated monocyclic rings that are notaromatic, such as 2- or 4-pyridones attached through the nitrogen orN-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils). Theterm also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl,2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl,7-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl,2-azabicyclo[2.2.2]octyl, and 3-azabicyclo[3.2.2]nonyl, andazabicyclo[2.2.1]heptanyl. The cycloheteroalkyl ring may be substitutedon the ring carbons and/or the ring nitrogens.

“Halogen” includes fluorine, chlorine, bromine and iodine.

When any variable (e.g., R¹, R^(d), etc.) occurs more than one time inany constituent or in formula I, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², etc.,are to be chosen in conformity with well-known principles of chemicalstructure connectivity and stability.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

Compounds of Formula I may contain one or more asymmetric centers andcan thus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Tautomers are defined as compounds that undergo rapid proton shifts fromone atom of the compound to another atom of the compound. Some of thecompounds described herein may exist as tautomers with different pointsof attachment of hydrogen. Such an example may be a ketone and its enolform known as keto-enol tautomers. The individual tautomers as well asmixture thereof are encompassed with compounds of Formula I.

Compounds of the Formula I may be separated into diastereoisomeric

pairs of enantiomers by, for example, fractional crystallization from asuitable solvent, for example MeOH or EtOAc or a mixture thereof. Thepair of enantiomers thus obtained may be separated into individualstereoisomers by conventional means, for example by the use of anoptically active amine as a resolving agent or on a chiral HPLC column.

Alternatively, any enantiomer of a compound of the general Formula I maybe obtained by stereospecific synthesis using optically pure startingmaterials or reagents of known configuration.

It is generally preferable to administer compounds of the presentinvention as enantiomerically pure formulations. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxiliary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like. The term “pharmaceutically acceptable salt”further includes all acceptable salts such as acetate, lactobionate,benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate,bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide,bromide, methylnitrate, calcium edetate, methylsulfate, camsylate,mucate, carbonate, napsylate, chloride, nitrate, clavulanate,N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate,edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate,esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate,polygalacturonate, gluconate, salicylate, glutamate, stearate,glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine,succinate, hydrobromide, tannate, hydrochloride, tartrate,hydroxynaphthoate, teoclate, iodide, tosylate, isothionate,triethiodide, lactate, panoate, valerate, and the like which can be usedas a dosage form for modifying the solubility or hydrolysischaracteristics or can be used in sustained release or pro-drugformulations.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Compounds of the present invention are modulators of the CB1 receptor.In particular, the compounds of structural formula I are antagonists orinverse agonists of the CB1 receptor.

An “agonist” is a compound (hormone, neurotransmitter or syntheticcompound) which binds to a receptor, inducing a conformational change inthe receptor which, in turn, produces a response such as contraction,relaxation, secretion, change in enzyme activity, etc. similar to thatelicited by the physiologically relevant agonist ligand(s) for thatreceptor. An “antagonist” is a compound which attenuates the effect ofan agonist. An “inverse agonist” is a compound which acts on a receptorbut produces the opposite effect produced by the agonist of theparticular receptor.

Compounds of this invention are modulators of the CB1 receptor and assuch are useful as centrally acting drugs in the treatment of psychosis,memory deficits, cognitive disorders, migraine, neuropathy,neuro-inflammatory disorders including multiple sclerosis andGuillain-Barre syndrome and the inflammatory sequelae of viralencephalitis, cerebral vascular accidents, and head trauma, anxietydisorders, stress, epilepsy, Parkinson's disease, movement disorders,and schizophrenia. The compounds are also useful for the treatment ofsubstance abuse disorders, particularly to opiates, alcohol, marijuana,and nicotine. The compounds are also useful for the treatment of obesityor eating disorders associated with excessive food intake andcomplications associated therewith. The compounds are also useful forthe treatment of constipation and chronic intestinal pseudo-obstruction.The compounds are also useful for the treatment of cirrhosis of theliver. The compounds are also useful for the treatment of asthma.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The administration of the compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to thepatient in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods of the presentinvention is determined via the use of well known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician in charge of the case, but depends on factorssuch as the exact disease to be treated, the severity of the disease andother diseases or conditions from which the patient suffers, the chosenroute of administration other drugs and treatments which the patient mayconcomitantly require, and other factors in the physician's judgment.

The utilities of the present compounds in these diseases or disordersmay be demonstrated in animal disease models that have been reported inthe literature. The following are examples of such animal diseasemodels: a) suppression of food intake and resultant weight loss in rats(Life Sciences 1998, 63, 113-117); b) reduction of sweet food intake inmarmosets (Behavioural Pharm. 1998, 9, 179-181); c) reduction of sucroseand ethanol intake in mice (Psychopharm. 1997, 132, 104-106); d)increased motor activity and place conditioning in rats (Psychopharm.1998, 135, 324-332; Psychopharmacol 2000, 151: 25-30); e) spontaneouslocomotor activity in mice (J. Pharm. Exp. Ther. 1996, 277, 586-594); f)reduction in opiate self-administration in mice (Sci. 1999, 283,401-404); g) bronchial hyperresponsiveness in sheep and guinea pigs asmodels for the various phases of asthma (for example, see W. M. Abrahamet at., “α₄-Integrins mediate antigen-induced late bronchial responsesand prolonged airway hyperresponsiveness in sheep.” J. Clin. Invest. 93,776 (1993) and A. A. Y. Milne and P. P. Piper, “Role of VLA-4 integrinin leucocyte recruitment and bronchial hyperresponsiveness in thegunea-pig.” Eur. J. Pharmacol., 282, 243 (1995)); h) mediation of thevasodilated state in advanced liver cirrhosis induced by carbontetrachloride (Nature Medicine, 2001, 7 (7), 827-832); i)amitriptyline-induced constipation in cynomolgus monkeys is beneficialfor the evaluation of laxatives (Biol. Pharm. Bulletin (Japan), 2000,23(5), 657-9); j) neuropathology of paediatric chronic intestinalpseudo-obstruction and animal models related to the neuropathology ofpaediatric chronic intestinal pseudo-obstruction (Journal of Pathology(England), 2001, 194 (3), 277-88).

The magnitude of prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound of Formula Iand its route of administration. It will also vary according to the age,weight and response of the individual patient. In general, the dailydose range lie within the range of from about 0.001 mg to about 100 mgper kg body weight of a mammal, preferably 0.01 mg to about 50 mg perkg, and most preferably 0.1 to 10 mg per kg, in single or divided doses.On the other hand, it may be necessary to use dosages outside theselimits in some cases.

For use where a composition for intravenous administration is employed,a suitable dosage range is from about 0.001 mg to about 25 mg(preferably from 0.01 mg to about 1 mg) of a compound of Formula I perkg of body weight per day and for preventive use from about 0.1 mg toabout 100 mg (preferably from about 1 mg to about 100 mg and morepreferably from about 1 mg to about 10 mg) of a compound of Formula Iper kg of body weight per day.

In the case where an oral composition is employed, a suitable dosagerange is, e.g. from about 0.01 mg to about 1000 mg of a compound ofFormula I per day, preferably from about 0.1.mg to about 10 mg per day.For oral administration, the compositions are preferably provided in theform of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05,0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 or1000 milligrams of the active ingredient for the symptomatic adjustmentof the dosage to the patient to be treated.

For the treatment of diseases of the eye, ophthalmic preparations forocular administration comprising 0.001-1% by weight solutions orsuspensions of the compounds of Formula I in an acceptable ophthalmicformulation may be used.

Another aspect of the present invention provides pharmaceuticalcompositions which comprises a compound of Formula I and apharmaceutically acceptable carrier. The term “composition”, as inpharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s), and the inert ingredient(s)(pharmaceutically acceptable excipients) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula I, additional active ingredient(s), and pharmaceuticallyacceptable excipients.

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dosage of a compound ofthe present invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof. In particular,the term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic bases or acids and organic bases or acids.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), ornasal administration, although the most suitable route in any given casewill depend on the nature and severity of the conditions being treatedand on the nature of the active ingredient. They may be convenientlypresented in unit dosage form and prepared by any of the methodswell-known in the art of pharmacy.

For administration by inhalation, the compounds of the present inventionare conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or nebulizers. The compounds may also bedelivered as powders which may be formulated and the powder compositionmay be inhaled with the aid of an insufflation powder inhaler device.The preferred delivery systems for inhalation are metered doseinhalation (MDI) aerosol, which may be formulated as a suspension orsolution of a compound of Formula I in suitable propellants, such asfluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol,which may be formulated as a dry powder of a compound of Formula I withor without additional excipients.

Suitable table topical formulations of a compound of formula I includetransdermal devices, aerosols, creams, solutions, ointments, gels,lotions, dusting powders, and the like. The topical pharmaceuticalcompositions containing the compounds of the present inventionordinarily include about 0.005% to 5% by weight of the active compoundin admixture with a pharmaceutically acceptable vehicle. Transdermalskin patches useful for administering the compounds of the presentinvention include those well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, capsules and tablets, with the solid oral preparationsbeing preferred over the liquid preparations. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit form in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds ofFormula I may also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules(including timed release and sustained release formulations), pills,cachets, powders, granules or tablets each containing a predeterminedamount of the active ingredient, as a powder or granules or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion or a water-in-oil liquid emulsion, includingelixirs, tinctures, solutions, suspensions, syrups and emulsions. Suchcompositions may be prepared by any of the methods of pharmacy but allmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation. For example, a tablet may beprepared by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine, the active ingredient in a free-flowing form suchas powder or granules, optionally mixed with a binder, lubricant, inertdiluent, surface active or dispersing agent. Molded tablets may be madeby molding in a suitable machine, a mixture of the powdered compoundmoistened with an inert liquid diluent. Desirably, each tablet containsfrom 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1, 2.5, 3, 5,6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 and1,000 milligrams of the active ingredient for the symptomatic adjustmentof the dosage to the patient to be treated, and each cachet or capsulecontains from about 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200,225, 500, 750 and 1,000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated.

Additional suitable means of administration of the compounds of thepresent invention include injection, intravenous bolus or infusion,intraperitoneal, subcutaneous, intramuscular and topical, with orwithout occlusion.

Exemplifying the invention is a pharmaceutical composition comprisingany of the compounds described above and a pharmaceutically acceptablecarrier. Also exemplifying the invention is a pharmaceutical compositionmade by combining any of the compounds described above and apharmaceutically acceptable carrier. An illustration of the invention isa process for making a pharmaceutical composition comprising combiningany of the compounds described above and a pharmaceutically acceptablecarrier.

The dose may be administered in a single daily dose or the total dailydosage may be administered in divided doses of two, three or four timesdaily. Furthermore, based on the properties of the individual compoundselected for administration, the dose may be administered lessfrequently, e.g., weekly, twice weekly, monthly, etc. The unit dosagewill, of course, be correspondingly larger for the less frequentadministration.

When administered via intranasal routes, transdermal routes, by rectalor vaginal suppositories, or through a continual intravenous solution,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

The following are examples of representative pharmaceutical dosage formsfor the compounds of Formula I:

Injectable Suspension (I.M.) mg/mL Compound of Formula I 10Methylcellulose 5.0 Tween 80 0.5 Benzyl alcohol 9.0 Benzalkoniumchloride 1.0 Water for injection to a total volume of 1 mL

Tablet mg/tablet Compound of Formula I 25 Microcrystalline Cellulose 415Povidone 14.0 Pregelatinized Starch 43.5 Magnesium Stearate 2.5 500

Capsule mg/capsule Compound of Formula I 25 Lactose Powder 573.5Magnesium Stearate 1.5 600

Aerosol Per canister Compound of Formula I   24 mg Lecithin, NF Liq.Conc.  1.2 mg Trichlorofluoromethane, NF 4.025 gDichlorodifluoromethane, NF 12.15 g

Compounds of Formula I may be used in combination with other drugs thatare used in the treatment/prevention/suppression or amelioration of thediseases or conditions for which compounds of Formula I are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefor, contemporaneously or sequentially with a compound ofFormula I. When a compound of Formula I is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound of Formula I is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of Formula I. Examples of other activeingredients that may be combined with a compound of Formula I include,but are not limited to: antipsychotic agents, cognition enhancingagents, anti-migraine agents, anti-asthmatic agents, antiinflammatoryagents, axioytics, anti-Parkinson's agents, anti-epileptics, anorecticagents, and serotonin reuptake inhibitors, and other anti-obesity agentswhich may be administered separately or in the same pharmaceuticalcompositions.

The present invention also provides a method for the treatment orprevention of a CB1 receptor modulator mediated disease, which methodcomprises administration to a patient in need of such treatment or atrisk of developing a CB1 receptor modulator mediated disease of anamount of a CB1 receptor modulator and an amount of one or more activeingredients, such that together they give effective relief.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a CB1 receptor modulator and oneor more active ingredients, together with at least one pharmaceuticallyacceptable carrier or excipient.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and one or more activeingredients for the manufacture of a medicament for the treatment orprevention of a CB1 receptor modulator mediated disease. In a further oralternative aspect of the present invention, there is therefore provideda product comprising a CB1 receptor modulator and one or more activeingredients as a combined preparation for simultaneous, separate orsequential use in the treatment or prevention of CB1 receptor modulatormediated disease. Such a combined preparation may be, for example, inthe form of a twin pack.

It will be appreciated that for the treatment or prevention of eatingdisorders, including obesity, bulimia nervosa and compulsive eatingdisorders, a compound of the present invention may be used inconjunction with other anorectic agents.

The present invention also provides a method for the treatment orprevention of eating disorders, which method comprises administration toa patient in need of such treatment an amount of a compound of thepresent invention and an amount of an anorectic agent, such thattogether they give effective relief.

Suitable anorectic agents of use in combination with a compound of thepresent invention include, but are not limited to, aminorex,amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex,cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; andpharmaceutically acceptable salts thereof.

A particularly suitable class of anorectic agent are the halogenatedamphetamine derivatives, including chlorphentermine, cloforex,clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine;and pharmaceutically acceptable salts thereof

Particularly preferred halogenated amphetamine derivatives of use incombination with a compound of the present invention include:fenfluramine and dexfenfluramine, and pharmaceutically acceptable saltsthereof.

It will be appreciated that for the treatment or prevention of obesity,the compounds of the present invention may also be used in combinationwith a selective serotonin reuptake inhibitor (SSRI).

The present invention also provides a method for the treatment orprevention of obesity, which method comprises administration to apatient in need of such treatment an amount of a compound of the presentinvention and an amount of an SSRI, such that together they giveeffective relief.

Suitable selective serotonin reuptake inhibitors of use in combinationwith a compound of the present invention include: fluoxetine,fluvoxamine, paroxetine, sertraline, and imipramine, andpharmaceutically acceptable salts thereof.

It will be appreciated that for the treatment or prevention of obesity,the compounds of the present invention may also be used in combinationwith an opioid antagonist.

The present invention also provides a method for the treatment orprevention of obesity, which method comprises administration to apatient in need of such treatment an amount of a compound of the presentinvention and an amount of an opioid antagonist, such that together theygive effective relief.

Suitable opioid antagonists of use in combination with a compound of thepresent invention include: naltrexone, 3-methoxynaltrexone, naloxone andnalmefene, and pharmaceutically acceptable salts thereof.

It will be appreciated that for the treatment or prevention of obesity,the compounds of the present invention may also be used in combinationwith inhibitors of the enzyme 11β-HSD1. Generally, glucocorticoidconcentrations are modulated by tissue-specific 11β-hydroxysteroiddehydrogenase enzymes. The 11β-hydroxysteroid dehydrogenase type 1enzyme (11β-HSD1) is a low affinity enzyme that generally uses NADP+ asa cofactor rather than NAD+ (Agarwal et al., 1989). In vitro studieshave shown that 11β-HSD1 is capable of acting as both a reductase and adehydrogenase. However, 11β-HSD1 in vivo generally acts as a reductase,converting 11-ketoglucocorticoids, such as cortisone, to11β-hydroxyglucocorticoids such as cortisol.

Excessive levels of cortisol have been associated with obesity, perhapsdue to increased hepatic gluconeogenesis. Thus, the administration of aneffective amount of an 11β-HSD1 inhibitor in combination with a CB1antagonist of the present invention may be useful in the treatment orcontrol of obesity. Particular inhibitors of 11β-HSD1 useful incombination with the compounds of the present invention include:3-(1-adamantyl)-4-ethyl-5-(ethylthio)-4H-1,2,4-triazole,3-(1-adamantyl)-5-(3,4,5-trimethoxyphenyl)-4methyl-4H-1,2,4-triazole,and3-adamantanyl-4,5,6,7,8,9,10,11,12,3a-decahydro-1,2,4-triazolo[4,3-a][11]annulene.

It will be appreciated that for the treatment or prevention of obesity,the compounds of the present invention may also be used in combinationwith another anti-obesity agent.

The present invention also provides a method for the treatment orprevention of obesity, which method comprises administration to apatient in need of such treatment an amount of a compound of the presentinvention and an amount of another anti-obesity agent, such thattogether they give effective relief.

Suitable anti-obesity agents of use in combination with a compound ofthe present invention, include, but are not limited to: 1) growthhormone secretagogues, such as those disclosed and specificallydescribed in U.S. Pat. No. 5,536,716; 2) growth hormone secretagoguereceptor agonists/antagonists, such as NN703, hexarelin, MK-0677,SM-130686, CP-424,391, L-692,429 and L-163,255, and such as thosedisclosed in U.S. Pat. No. 6,358,951, U.S. Patent Application Nos.2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO02/32888; 3) melanocortin agonists, such as Melanotan II or thosedescribed in WO 99/64002 and WO 00/74679; 4) Mc4r (melanocortin 4receptor) agonists, such as CHIR86036 (Chiron), ME-10142, and ME-10145(Melacure), and those disclosed in PCT Application Nos. WO 01/991752, WO01/74844, WO 02/12166, WO 02/11715, and WO 02/12178; 5) β-3 agonists,such as AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790,BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243,Trecadrine, Zeneca D7114, SR 59119A, and such as those disclosed in U.S.Pat. No. 5,705,515, and U.S. Pat. No. 5,451,677 and PCT PatentPublications WO94/18161, WO95/29159, WO97/46556, WO98/04526 andWO98/32753, WO 01/74782, and WO 02/32897; 6) 5HT-2 agonists; 7) 5HT2C(serotonin receptor 2C) agonists, such as BVT933, DPCA37215, WAY161503,R-1065, and those disclosed in U.S. Pat. No. 3,914,250, and PCTApplication Nos. WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO02/44152, WO 02/51844, WO 02/40456, and WO 02/40457; 8) orexinantagonists, such as SB-334867-A, and those disclosed in PCT PatentApplication Nos. WO 01/96302, WO 01/68609, WO 02/51232, and WO 02/51838;9) melanin concentrating hormone antagonists; 10) melanin-concentratinghormone 1 receptor (MCH1R) antagonists, such as T-226296 (Takeda), andthose disclosed in PCT Patent Application Nos. WO 01/82925, WO 01/87834,WO 02/06245, WO 02/04433, and WO 02/51809, and Japanese PatentApplication No. JP 13226269; 11) melanin-concentrating hormone 2receptor (MCH2R) agonist/antagonists; 12) galanin antagonists; 13) CCKagonists; 14) CCK-A (cholecystokinin-A) agonists, such as AR-R 15849, GI181771, JMV-180, A-71378, A-71623 and SR146131, and those discribed inU.S. Pat. No. 5,739,106; 15) GLP-1 agonists; 16) corticotropin-releasinghormone agonists; 17) NPY 5 antagonists, such as GW-569180A, GW-594884A,GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91,GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A andJCF-104, and those disclosed in U.S. Pat. Nos. 6,140,354, 6,191,160,6,313,298, 6,337,332, 6,329,395, 6,326,375, 6,335,345, and 6,340,683,European Patent Nos. EP-01010691, and EP-01044970, and PCT PatentPublication Nos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO97/20823, WO 98/27063, WO 00/64880, WO 00/68197, WO 00/69849, WO01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01/07409, WO01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO02/49648; 18) NPY 1 antagonists, such as BIBP3226, J-115814, BIBO 3304,LY-357897, CP-671906, GI-264879A, and those disclosed in U.S. Pat. No.6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; 19)histamine receptor-3 (H3) modulators; 20) histamine receptor-3 (H3)antagonists/inverse agonists, such as hioperamide,3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit,iodophenpropit, imoproxifan, GT2394 (Gliatech), and those described anddisclosed in PCT Application No. WO 02/15905, andO-[3-(1H-imidazol-4-yl)propanol]-carbamates (Kiec-Kononowicz, K. et al.,Pharmazie, 55:349-55 (2000)), piperidine-containing histamineH3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56:927-32(2001), benzophenone derivatives and related compounds (Sasse, A. etal., Arch. Pharm. (Weinheim) 334:45-52 (2001)), substitutedN-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55:83-6 (2000)),and proxifan derivatives (Sasse, A. et al., J. Med. Chem. 43:3335-43(2000)); 21) β-hydroxy steroid dehydrogenase-1 inhibitors (β-HSD-1); 22)PDE (phosphodiesterase) inhibitors, such as theophylline,pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide,rolipram, and cilomilast; 23) phosphodiesterase-3B (PDE3B) inhibitors;24) NE (norepinephrine) transport inhibitors, such as GW 320659,despiramine, talsupram, and nomifensine; 25) non-selectiveserotonin/norepinephrine transport inhibitors, such as sibutramine orfenfluramine; 26) ghrelin antagonists, such as those disclosed in PCTApplication Nos. WO 01/87335, and WO 02/08250; 27) leptin, includingrecombinant human leptin (PEG-OB, Hoffman La Roche) and recombinantmethionyl human leptin (Amgen); 28) leptin derivatives, such as thosedisclosed in U.S. Pat. Nos. 5,552,524, 5,552,523, 5,552,522, 5,521,283,and PCT International Publication Nos. WO 96/23513, WO 96/23514, WO96/23515, WO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519, and WO96/23520; 29) BRS3 (bombesin receptor subtype 3) agonists; 30) CNTF(Ciliary neurotrophic factors), such as GI-181771 (Glaxo-SmithKline),SR146131 (Sanofi Synthelabo), butabindide, PD170,292, and PD 149164(Pfizer); 31) CNTF derivatives, such as axokine (Regeneron), and thosedisclosed in PCT Application Nos. WO 94/09134, WO 98/22128, and WO99/43813; 32) monoamine reuptake inhibitors, such as those disclosed inPCT Application Nos. WO 01/27068, and WO 01/62341; 33) UCP-1 (uncouplingprotein-1), 2, or 3 activators, such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), retinoic acid, and those disclosed in PCT PatentApplication No. WO 99/00123; 34) thyroid hormone β agonists, such asKB-2611 (KaroBioBMS), and those disclosed in PCT Application No. WO02/15845, and Japanese Patent Application No. JP 2000256190; 35) FAS(fatty acid synthase) inhibitors, such as Cerulenin and C75; 36) DGAT1(diacylglycerol acyltransferase 1) inhibitors; 37) DGAT2 (diacylglycerolacyltransferase 2) inhibitors; 38) ACC2 (acetyl-CoA carboxylase-2)inhibitors; 39) glucocorticoid antagonists; 40) acyl-estrogens, such asoleoyl-estrone, disclosed in del Mar-Grasa, M. et al., Obesity Research,9:202-9 (2001); 41) lipase inhibitors, such as orlistat (Xenical®),Triton WR1339, RHC80267, lipstatin, tetrahydrolipstatin, teasaponin,diethylumbelliferyl phosphate, and those disclosed in PCT ApplicationNo. WO 01/77094; 42) fatty acid transporter inhibitors; 43)dicarboxylate transporter inhibitors; 44) glucose transporterinhibitors; 45) phosphate transporter inhibitors; 46) serotonin reuptakeinhibitors, such as those disclosed in U.S. Pat. No. 6,365,633, and PCTPatent Application Nos. WO 01/27060, and WO 01/162341; 47) Metformin(Glucophage®); and/or 48) Topiramate (Topimax®).

Specific NPY5 antagonists of use in combination with a compound of thepresent invention are selected from the group consisting of:

-   (1)    3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,-   (2)    3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboximide,-   (3)    N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,-   (4)    trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,-   (5)    trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,-   (6)    trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaiso-benzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,-   (7)    trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,-   (8)    trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,-   (9)    trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,-   (10)    trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,-   (11)    trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,-   (12)    trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,-   (13)    trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,    and pharmaceutically acceptable salts and esters thereof.

“Obesity” is a condition in which there is an excess of body fat. Theoperational definition of obesity is based on the Body Mass Index (BMI),which is calculated as body weight per height in meters squared (kg/m²).“Obesity” refers to a condition whereby an otherwise healthy subject hasa Body Mass Index (BMI) greater than or equal to 30 kg/m², or acondition whereby a subject with at least one co-morbidity has a BMIgreater than or equal to 27 kg/m². An “obese subject” is an otherwisehealthy subject with a Body Mass Index (BMI) greater than or equal to 30kg/m² or a subject with at least one co-morbidity with a BMI greaterthan or equal to 27 kg/m². A “subject at risk for obesity” is anotherwise healthy subject with a BMI of 25 kg/m² to less than 30 kg/m²or a subject with at least one co-morbidity with a BMI of 25 kg/m² toless than 27 kg/m².

The increased risks associated with obesity occur at a lower Body MassIndex (BMI) in Asians. In Asian countries, including Japan, “obesity”refers to a condition whereby a subject with at least oneobesity-induced or obesity-related co-morbidity that requires weightreduction or that would be improved by weight reduction, has a BMIgreater than or equal to 25 kg/m². In Asian countries, including Japan,an “obese subject” refers to a subject with at least one obesity-inducedor obesity-related co-morbidity that requires weight reduction or thatwould be improved by weight reduction, with a BMI greater than or equalto 25 kg/m². In Asian countries, a “subject at risk for obesity” is asubject with a BMI of greater than 23 kg/m² to less than 25 kg/m².

As used herein, the term “obesity” is meant to encompass all of theabove definitions of obesity.

Obesity-induced or obesity-related co-morbidities include, but are notlimited to, diabetes, non-insulin dependent diabetes mellitus-type 2,impaired glucose tolerance, impaired fasting glucose, insulin resistancesyndrome, dyslipidemia, hypertension, hyperuricacidemia, gout, coronaryartery disease, myocardial infarction, angina pectoris sleep apneasyndrome, Pickwickian syndrome, fatty liver; cerebral infarction,cerebral thrombosis, transient ischemic attack, orthopedic disorders,arthritis deformans, lumbodynia, emmeniopathy, and infertility. Inparticular, co-morbidities include: hypertension, hyperlipidemia,dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea,diabetes mellitus, and other obesity-related conditions.

“Treatment” (of obesity and obesity-related disorders) refers to theadministration of the compounds or compositions of the present inventionto reduce or maintain the body weight of an obese subject. One outcomeof treatment may be reducing the body weight of an obese subjectrelative to that subject's body weight immediately before theadministration of the compounds or compositions of the presentinvention. Another outcome of treatment may be preventing regain of bodyweight previously lost as a result of diet, exercise, orpharmacotherapy. Another outcome of treatment may be decreasing theoccurrence of and/or the severity of obesity-related diseases. Thetreatment may suitably result in a reduction in food or calorie intakeby the subject, including a reduction in total food intake, or areduction of intake of specific components of the diet such ascarbohydrates or fats; and/or the inhibition of nutrient absorption;and/or the inhibition of the reduction of metabolic rate; and in weightreduction in patients in need thereof. The treatment may also result inan alteration of metabolic rate, such as an increase in metabolic rate,rather than or in addition to an inhibition of the reduction ofmetabolic rate; and/or in minimization of the metabolic resistance thatnormally results from weight loss.

“Prevention” (of obesity and obesity-related disorders) refers to theadministration of the compounds or compositions of the present inventionto reduce or maintain the body weight of a subject at risk for obesity.One outcome of prevention may be reducing the body weight of a subjectat risk for obesity relative to that subject's body weight immediatelybefore the administration of the compounds or compositions of thepresent invention. Another outcome of prevention may be preventing bodyweight regain of body weight previously lost as a result of diet,exercise, or pharmacotherapy. Another outcome of prevention may bepreventing obesity from occurring if the treatment is administered priorto the onset of obesity in a subject at risk for obesity. Anotheroutcome of prevention may be decreasing the occurrence and/or severityof obesity-related disorders if the treatment is administered prior tothe onset of obesity in a subject at risk for obesity. Moreover, iftreatment is commenced in already obese subjects, such treatment mayprevent the occurrence, progression or severity of obesity-relateddisorders, such as, but not limited to, arteriosclerosis, Type IIdiabetes, polycystic ovarian disease, cardiovascular diseases,osteoarthritis, dermatological disorders, hypertension, insulinresistance, hypercholesterolemia, hypertriglyceridemia, andcholelithiasis.

Obesity-related disorders are associated with, caused by, or result fromobesity. Examples of obesity-related disorders include overeating andbulimia, hypertension, diabetes, elevated plasma insulin concentrationsand insulin resistance, dyslipidemias, hyperlipidemia, endometrial,breast, prostate and colon cancer, osteoarthritis, obstructive sleepapnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythmsand arrythmias, myocardial infarction, congestive heart failure,coronary heart disease, sudden death, stroke, polycystic ovariandisease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich'ssyndrome, GH-deficient subjects, normal variant short stature, Turner'ssyndrome, and other pathological conditions showing reduced metabolicactivity or a decrease in resting energy expenditure as a percentage oftotal fat-free mass, e.g, children with acute lymphoblastic leukemia.Further examples of obesity-related disorders are metabolic syndrome,also known as syndrome X, insulin resistance syndrome, sexual andreproductive dysfunction, such as infertility, hypogonadism in males andhirsutism in females, gastrointestinal motility disorders, such asobesity-related gastro-esophageal reflux, respiratory disorders, such asobesity-hypoventilation syndrome (Pickwickian syndrome), cardiovasculardisorders, inflammation, such as systemic inflammation of thevasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia,lower back pain, gallbladder disease, gout, and kidney cancer. Thecompositions of the present invention are also useful for reducing therisk of secondary outcomes of obesity, such as reducing the risk of leftventricular hypertrophy.

The term “diabetes,” as used herein, includes both insulin-dependentdiabetes mellitus (i.e., IDDM, also known as type I diabetes) andnon-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as TypeII diabetes. Type I diabetes, or insulin-dependent diabetes, is theresult of an absolute deficiency of insulin, the hormone which regulatesglucose utilization. Type II diabetes, or insulin-independent diabetes(i.e., non-insulin-dependent diabetes mellitus), often occurs in theface of normal, or even elevated levels of insulin and appears to be theresult of the inability of tissues to respond appropriately to insulin.Most of the Type II diabetics are also obese. The compounds andcompositions of the present invention are useful for treating both TypeI and Type II diabetes. The compounds and compositions are especiallyeffective for treating Type II diabetes. The compounds and compositionsof the present invention are also useful for treating and/or preventinggestational diabetes mellitus.

It will be appreciated that for the treatment or prevention of migraine,a compound of the present invention may be used in conjunction withother anti-migraine agents, such as ergotamines or 5-HT₁ agonists,especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.

It will be appreciated that for the treatment of depression or anxiety,a compound of the present invention may be used in conjunction withother anti-depressant or anti-anxiety agents.

Suitable classes of anti-depressant agents include norepinephrinereuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs),monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamineoxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors(SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists andatypical anti-depressants.

Suitable norepinephrine reuptake inhibitors include tertiary aminetricyclics and secondary amine tricyclics. Suitable examples of tertiaryamine tricyclics include: amitriptyline, clomipramine, doxepin,imipramine and trimipramine, and pharmaceutically acceptable saltsthereof. Suitable examples of secondary amine tricyclics include:amoxapine, desipramine, maprotiline, nortriptyline and protriptyline,and pharmaceutically acceptable salts thereof.

Suitable selective serotonin reuptake inhibitors include: fluoxetine,fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptablesalts thereof.

Suitable monoamine oxidase inhibitors include: isocarboxazid,phenelzine, tranylcypromine and selegiline, and pharmaceuticallyacceptable salts thereof.

Suitable reversible inhibitors of monoamine oxidase include:moclobemide, and pharmaceutically acceptable salts thereof.

Suitable serotonin and noradrenaline reuptake inhibitors of use in thepresent invention include: venlafaxine, and pharmaceutically acceptablesalts thereof.

Suitable CRF antagonists include those compounds described inInternational Patent Specification Nos. WO 94/13643, WO 94/13644, WO94/13661, WO 94/13676 and WO 94/13677.

Suitable neurokinin-1 receptor antagonists may be peptidal ornon-peptidal in nature, however, the use of a non-peptidal neurokinin-1receptor antagonist is preferred. In a preferred embodiment, theneurokinin-1 receptor antagonist is a CNS-penetrant neurokinin-1receptor antagonist. In addition, for convenience the use of an orallyactive neurokinin-1 receptor antagonist is preferred. To facilitatedosing, it is also preferred that the neurokinin-1 receptor antagonistis a long acting neurokinin-1 receptor antagonist. An especiallypreferred class of neurokinin-1 receptor antagonists of use in thepresent invention are those compounds which are orally active and longacting.

Neurokinin-1 receptor antagonists of use in the present invention arefully described, for example, in U.S. Pat. Nos. 5,162,339, 5,232,929,5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833,5,637,699; European Patent Publication Nos. EP 0 360 390, 0 394 989, 0428 434, 0 429 366, 0 430 771, 0 436 334, 0 443 132, 0 482 539, 0 498069, 0 499 313, 0 512 901, 0 512 902, 0 514 273, 0 514 274, 0 514 275, 0514 276, 0 515 681, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532456, 0 533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0 585 913, 0590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 709 375, 0 709 376, 0714 891, 0 723 959, 0 733 632 and 0 776 893; PCT International PatentPublication Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688,92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677,92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170,93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064,93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461,94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843,94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639,94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735,94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886,95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382,95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798,95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193,96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197,96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385,96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362,97/18206, 97/19084, 97/19942, 97/21702, 97/49710, 98/24438-98/24441,98/24442-98/24445, 02/16343, and 02/16344; and in British PatentPublication Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774,2 292 144, 2 293 168, 2 293 169, and 2 302 689.

Specific neurokinin-1 receptor antagonists of use in the presentinvention include:

-   (±)-(2R3R,2S3S)-N-{[2-cyclopropoxy-5-(trifluoromethoxy)-phenyl]methyl}-2-phenylpiperidin-3amine;-   2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;-   2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4triazolo)methyl)morpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3(S)-phenylmorpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3(S)-(4-fluorophenyl)morpholine;-   (3S,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;-   (3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;-   2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine;-   2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;    or a pharmaceutically acceptable salt thereof.

Suitable atypical anti-depressants include: bupropion, lithium,nefazodone, trazodone and viloxazine, and pharmaceutically acceptablesalts thereof.

Suitable classes of anti-anxiety agents include benzodiazepines and5-HT_(1A) agonists or antagonists, especially 5-HT_(1A) partialagonists, and corticotropin releasing factor (CRF) antagonists.

Suitable benzodiazepines include: alprazolam, chlordiazepoxide,clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam andprazepam, and pharmaceutically acceptable salts thereof.

Suitable 5-HT_(1A) receptor agonists or antagonists include, inparticular, the 5-HT_(1A) receptor partial agonists buspirone,flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptablesalts thereof.

Suitable corticotropin releasing factor (CRF) antagonists include thosepreviously discussed herein.

As used herein, the term “substance abuse disorders” includes substancedependence or abuse with or without physiological dependence. Thesubstances associated with these disorders are: alcohol, amphetamines(or amphetamine-like substances), caffeine, cannabis, cocaine,hallucinogens, inhalants, marijuana, nicotine, opioids, phencyclidine(or phencyclidine-like compounds), sedative-hypnotics orbenzodiazepines, and other (or unknown) substances and combinations ofall of the above.

In particular, the term “substance abuse disorders” includes drugwithdrawal disorders such as alcohol withdrawal with or withoutperceptual disturbances; alcohol withdrawal delirium; amphetaminewithdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal;sedative, hypnotic or anxiolytic withdrawal with or without perceptualdisturbances; sedative, hypnotic or anxiolytic withdrawal delirium; andwithdrawal symptoms due to other substances. It will be appreciated thatreference to treatment of nicotine withdrawal includes the treatment ofsymptoms associated with smoking cessation.

Other “substance abuse disorders” include substance-induced anxietydisorder with onset during withdrawal; substance-induced mood disorderwith onset during withdrawal; and substance-induced sleep disorder withonset during withdrawal.

It will be appreciated that a combination of a conventionalantipsychotic drug with a CB1 receptor modulator may provide an enhancedeffect in the treatment of mania. Such a combination would be expectedto provide for a rapid onset of action to treat a manic episode therebyenabling prescription on an “as needed basis”. Furthermore, such acombination may enable a lower dose of the antispychotic agent to beused without compromising the efficacy of the antipsychotic agent,thereby minimizing the risk of adverse side-effects. A yet furtheradvantage of such a combination is that, due to the action of the CB1receptor modulator, adverse side-effects caused by the antipsychoticagent such as acute dystonias, dyskinesias, akathesia and tremor may bereduced or prevented.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and an antipsychotic agentfor the manufacture of a medicament for the treatment or prevention ofmania.

The present invention also provides a method for the treatment orprevention of mania, which method comprises administration to a patientin need of such treatment or at risk of developing mania of an amount ofa CB1 receptor modulator and an amount of an antipsychotic agent, suchthat together they give effective relief.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a CB1 receptor modulator and anantipsychotic agent, together with at least one pharmaceuticallyacceptable carrier or excipient.

It will be appreciated that the CB1 receptor modulator and theantipsychotic agent may be present as a combined preparation forsimultaneous, separate or sequential use for the treatment or preventionof mania. Such combined preparations may be, for example, in the form ofa twin pack.

In a further or alternative aspect of the present invention, there istherefore provided a product comprising a CB1 receptor modulator and anantipsychotic agent as a combined preparation for simultaneous, separateor sequential use in the treatment or prevention of mania.

It will be appreciated that when using a combination of the presentinvention, the CB1 receptor modulator and the antipsychotic agent may bein the same pharmaceutically acceptable carrier and thereforeadministered simultaneously. They may be in separate pharmaceuticalcarriers such as conventional oral dosage forms which are takensimultaneously. The term “combination” also refers to the case where thecompounds are provided in separate dosage forms and are administeredsequentially. Therefore, by way of example, the antipsychotic agent maybe administered as a tablet and then, within a reasonable period oftime, the CB1 receptor modulator may be administered either as an oraldosage form such as a tablet or a fast-dissolving oral dosage form. By a“fast-dissolving oral formulation” is meant, an oral delivery form whichwhen placed on the tongue of a patient, dissolves within about 10seconds.

Included within the scope of the present invention is the use of CB1receptor modulators in combination with an antipsychotic agent in thetreatment or prevention of hypomania.

It will be appreciated that a combination of a conventionalantipsychotic drug with a CB1 receptor modulator may provide an enhancedeffect in the treatment of schizophrenic disorders. Such a combinationwould be expected to provide for a rapid onset of action to treatschizophrenic symptoms thereby enabling prescription on an “as neededbasis”. Furthermore, such a combination may enable a lower dose of theCNS agent to be used without compromising the efficacy of theantipsychotic agent, thereby minimizing the risk of adverseside-effects. A yet further advantage of such a combination is that, dueto the action of the CB1 receptor modulator, adverse side-effects causedby the antipsychotic agent such as acute dystonias, dyskinesias,akathesia and tremor may be reduced or prevented.

As used herein, the term “schizophrenic disorders” includes paranoid,disorganized, catatonic, undifferentiated and residual schizophrenia;schizophreniform disorder; schizoaffective disorder; delusionaldisorder; brief psychotic disorder; shared psychotic disorder;substance-induced psychotic disorder; and psychotic disorder nototherwise specified.

Other conditions commonly associated with schizophrenic disordersinclude self-injurious behavior (e.g. Lesch-Nyhan syndrome) and suicidalgestures.

Suitable antipsychotic agents of use in combination with a CB1 receptormodulator include the phenothiazine, thioxanthene, heterocyclicdibenzazepine, butyrophenone, diphenylbutylpiperidine and indoloneclasses of antipsychotic agent. Suitable examples of phenothiazinesinclude chlorpromazine, mesoridazine, thioridazine, acetophenazine,fluphenazine, perphenazine and trifluoperazine. Suitable examples ofthioxanthenes include chlorprothixene and thiothixene. Suitable examplesof dibenzazepines include clozapine and olanzapine. An example of abutyrophenone is haloperidol. An example of a diphenylbutylpiperidine ispimozide. An example of an indolone is molindolone. Other antipsychoticagents include loxapine, sulpiride and risperidone. It will beappreciated that the antipsychotic agents when used in combination witha CB1 receptor modulator may be in the form of a pharmaceuticallyacceptable salt, for example, chlorpromazine hydrochloride, mesoridazinebesylate, thioridazine hydrochloride, acetophenazine maleate,fluphenazine hydrochloride, flurphenazine enathate, fluphenazinedecanoate, trifluoperazine hydrochloride, thiothixene hydrochloride,haloperidol decanoate, loxapine succinate and molindone hydrochloride.Perphenazine, chlorprothixene, clozapine, olanzapine, haloperidol,pimozide and risperidone are commonly used in a non-salt form.

Other classes of antipsychotic agent of use in combination with a CB1receptor modulator include dopamine receptor antagonists, especially D2,D3 and D4 dopamine receptor antagonists, and muscarinic m1 receptoragonists. An example of a D3 dopamine receptor antagonist is thecompound PNU-99194A. An example of a D4 dopamine receptor antagonist isPNU-101387. An example of a muscarinic m1 receptor agonist isxanomeline.

Another class of antipsychotic agent of use in combination with a CB1receptor modulator is the 5-HT_(2A) receptor antagonists, examples ofwhich include MDL100907 and fananserin. Also of use in combination witha CB1 receptor modulator are the serotonin dopamine antagonists (SDAs)which are believed to combine 5-HT_(2A) and dopamine receptor antagonistactivity, examples of which include olanzapine and ziperasidone.

Still further, NK-1 receptor antagonists may be favorably employed withthe CB1 receptor modulators of the present invention. Preferred NK-1receptor antagonists for use in the present invention are selected fromthe classes of compounds described in European Patent Specification No.0 577 394, and International Patent Specification Nos. 95/08549,95/18124, 95/23798, 96/05181, and 98/49710 (Application No.PCT/GB97/01630). The preparation of such compounds is fully described inthe aforementioned publications.

Particularly preferred NK-1 receptor antagonists of use in the presentinvention include:(3S,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;(3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;(±)-(2R3R,2S3S)-N-{[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]methyl}-2-phenylpiperidin-3amine;2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)-3-(S)-(4-fluorophenyl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine;2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5oxo-4H-1,2,4triazolo)methyl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholineor a pharmaceutically acceptable salt thereof.

It will be appreciated that a combination of a conventionalanti-asthmatic drug with a CB1 receptor modulator may provide anenhanced effect in the treatment of asthma.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and an anti-asthmatic agentfor the manufacture of a medicament for the treatment or prevention ofasthma.

The present invention also provides a method for the treatment orprevention of asthma, which method comprises administration to a patientin need of such treatment an amount of a compound of the presentinvention and an amount of an anti-asthmatic agent, such that togetherthey give effective relief.

Suitable anti-asthmatic agents of use in combination with a compound ofthe present invention include, but are not limited to: (a) VLA-4antagonists such as natalizumab and the compounds described in U.S. Pat.No. 5,510,332, WO97/03094, WO97/02289, WO96/40781, WO96/22966,WO96/20216, WO96/01644, WO96/06108, WO95/15973 and WO96/31206; (b)steroids and corticosteroids such as beclomethasone, methylprednisolone,betamethasone, prednisone, dexamethasone, and hydrocortisone; (c)antihistamines (H1-histamine antagonists) such as bromopheniramine,chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine,diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine,methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine,antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine,desloratadine, cetirizine, fexofenadine, descarboethoxyloratadine, andthe like; (d) non-steroidal anti-asthmatics including β2-agonists (suchas terbutaline, metaproterenol, fenoterol, isoetharine, albuterol,bitolterol, salmeterol, epinephrine, and pirbuterol), theophylline,cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists(such as zafirlukast, montelukast, pranlukast, iralukast, pobilukast,and SKB-106,203), and leukotriene biosynthesis inhibitors (such aszileuton and BAY-1005); (e) anti-cholinergic agents including muscarinicantagonists (such as ipratropium bromide and atropine); (f) antagonistsof the chemokine receptors, especially CCR-1, CCR-2, and CCR-3; (g)immunosuppressants such as cyclosporin, tacrolimus, rapamycin and otherFK-506 type immunosuppressants; (h) non-steroidal antiinflammatoryagents (NSAIDs) such as propionic acid derivatives (alminoprofen,benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen,flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen,oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, andtioxaprofen), acetic acid derivatives (indomethacin, acemetacin,alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid,fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac,tolmetin, zidometacin, and zomepirac), fenamic acid derivatives(flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid andtolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal andflufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican),salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones(apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone,phenylbutazone); (i) cyclooxygenase-2 (COX-2) inhibitors such ascelecoxib; (j) anti-diabetic agents such as insulin, sulfonylureas,biguanides (metformin), a-glucosidase inhibitors (acarbose) andglitazones (troglitazone, pioglitazone, englitazone, MCC-555, BRL49653and the like); (k) preparations of interferon beta (interferon beta-1a,interferon beta-1b); (l) other compounds such as 5-aminosalicylic acidand prodrugs thereof, and pharmaceutically acceptable salts thereof.

It will be appreciated that a combination of a conventionalanti-constipation drug with a CB1 receptor modulator may provide anenhanced effect in the treatment of constipation.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and an anti-constipationagent for the manufacture of a medicament for the treatment orprevention of constipation.

The present invention also provides a method for the treatment orprevention of constipation, which method comprises administration to apatient in need of such treatment an amount of a compound of the presentinvention and an amount of an anti-constipation agent, such thattogether they give effective relief.

It will be appreciated that a combination of a conventionalanti-constipation drug with a CB1 receptor modulator may provide anenhanced effect in the treatment of chronic intestinalpseudo-obstruction.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and an anti-constipationagent for the manufacture of a medicament for the treatment orprevention of chronic intestinal pseudo-obstruction.

The present invention also provides a method for the treatment orprevention of chronic intestinal pseudo-obstruction, which methodcomprises administration to a patient in need of such treatment anamount of a compound of the present invention and an amount of ananti-constipation agent, such that together they give effective relief.

Suitable anti-constipation agents of use in combination with a compoundof the present invention include, but are not limited to, osmoticagents, laxatives and detergent laxatives (or wetting agents), bulkingagents, and stimulants; and pharmaceutically acceptable salts thereof.

A particularly suitable class of osmotic agents include, but are notlimited to sorbitol, lactulose, polyethylene glycol, magnesium,phosphate, and sulfate; and pharmaceutically acceptable salts thereof.

A particularly suitable class of laxatives and detergent laxatives,include, but are not limited to, magnesium, and docusate sodium; andpharmaceutically acceptable salts thereof.

A particularly suitable class of bulking agents include, but are notlimited to, psyllium, methylcellulose, and calcium polycarbophil; andpharmaceutically acceptable salts thereof.

A particularly suitable class of stimulants include, but are not limitedto, anthroquinones, and phenolphthalein; and pharmaceutically acceptablesalts thereof.

It will be appreciated that a combination of a conventionalanti-cirrhosis drug with a CB1 receptor modulator may provide anenhanced effect in the treatment of cirrhosis of the liver.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and an anti-cirrhosis agentfor the manufacture of a medicament for the treatment or prevention ofcirrhosis of the liver.

The present invention also provides a method for the treatment orprevention of cirrhosis of the liver, which method comprisesadministration to a patient in need of such treatment an amount of acompound of the present invention and an anti-cirrhosis agent, such thattogether they give effective relief.

Suitable anti-cirrhosis agents of use in combination with a compound ofthe present invention include, but are not limited to, corticosteroids,penicillamine, colchicine, interferon-γ, 2-oxoglutarate analogs,prostaglandin analogs, and other anti-inflammatory drugs andantimetabolites such as azathioprine, methotrexate, leflunamide,indomethacin, naproxen, and 6-mercaptopurine; and pharmaceuticallyacceptable salts thereof.

The method of treatment of this invention comprises a method ofmodulating the CB1 receptor and treating CB1 receptor mediated diseasesby administering to a patient in need of such treatment a non-toxictherapeutically effective amount of a compound of this invention thatselectively antagonizes the CB1 receptor in preference to the other CBor G-protein coupled receptors.

The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician, which includes alleviation of the symptoms of the disorderbeing treated. The novel mehtods of treatment of this invention are fordisorders known to those skilled in the art. The term “mammal” includeshumans.

The weight ratio of the compound of the Formula I to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the Formula I is combined with a β-3 agonistthe weight ratio of the compound of the Formula I to the β-3 agonistwill generally range from about 1000:1 to about 1:1000, preferably about200:1 to about 1:200. Combinations of a compound of the Formula I andother active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

Abbreviations used in the following Schemes and Examples:

aq.: aqueous API-ES: atmospheric pressure ionization-electrospray (massspectrum term) DEAD: diethyl azodicarboxylate DMAP:4-dimethylaminopyridine DMF: dimethylformamide DMSO: dimethylsulfoxideEDC: 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride EPA:ethylene polyacrylamide (a plastic) EtOAc: ethyl acetate g: gram h:hours Hex: hexane HOBt: 1-hydroxybenzotriazole HPLC: high pressureliquid chromatography HPLC/MS: high pressure liquid chromatography/massspectrum in. vacuo: rotoevaporation IPAC or IPAc: isopropyl acetateKHMDS: potassium hexamethyldisilazide LC: Liquid chromatography LC/MS,LC-MS: liquid chromatography-mass spectrum LDA: lithium diisopropylamide M: molar Me: methyl MeOH: methanol MHz: megahertz min: minute mL:milliliter mmol: millimole MS or ms: mass spectrum N: normal NaHMDS:sodium hexamethyldisilazide NMR: nuclear magnetic resonance PyBOP:(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphateR_(t): retention time rt or RT: room temperature TFA: trifluoroaceticacid THF: tetrahydrofuran. TLC: thin layer chromatography

Compounds of the present invention may be prepared by proceduresillustrated in the accompanying schemes.

In Scheme 1, an appropriately substituted amine A is reacted with acarboxylic acid B under standard amide bond forming conditions to affordthe arylamide C. In order to illustrate the invention, the followingexamples are included. These examples do not limit the invention. Theyare only meant to suggest a method of reducing the invention topractice. Those skilled in the art may find other methods of practicingthe invention which are readily apparent to them. However, those methodsare also deemed to be within the scope of this invention.

General Procedures

The LC/MS analyses were preformed using a MICROMASS ZMD massspectrometer coupled to an AGILENT 1100 Series HPLC utilizing a YMCODS-A 4.6×50 mm column eluting at 2.5 mL/min with a solvent gradient of10 to 95% B over 4.5 min, followed by 0.5 min at 95% B: solvent A=0.06%TFA in water; solvent B=0.05% TFA in acetonitrile. ¹H-NMR spectra wereobtained on a 500 MHz VARIAN Spectrometer in CDCl₃ or CD₃OD as indicatedand chemical shifts are reported as δ using the solvent peak asreference and coupling constants are reported in hertz (Hz).

REFERENCE EXAMPLE 1

N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride

The preparation of the two diastereomers (alpha and beta) ofN-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride salt hasbeen disclosed (Schultz, E. M, et al. J. Med Chem. 1967, 10, 717).Diastereomer α: LC-MS: calculated for C₁₆H₁₇Cl₂N 293, observed m/e 294(M+H)⁺ (R_(t) 2.5 min). Diastereomer β: LC-MS: calculated for C₁₆H₁₇Cl₂N293, observed m/e 294 (M+H)⁺ (R_(t) 2.2 min).

The amines of Reference Examples 2-9 were prepared by the sameprocedures described in Reference Example 1:

REFERENCE EXAMPLE 2

2-Amino-3,4-diphenylbutane hydrochloride salt

Diastereomer α:

LC-MS: calculated for C₁₆H₁₉N 225, observed m/e 226 (M+H)⁺ (2.0 min).

Diastereomer β:

LC-MS: calculated for C₁₆H₁₉N 225, observed m/e 226 (M+H)⁺ (1.9 min).

REFERENCE EXAMPLE 3

3-Amino-1,2-diphenylpentane hydrochloride salt

Diastereomer α:

LC-MS: calculated for C₁₇H₂₁N 239, observed m/e 240 (M+H)⁺ (2.1 min).

Diastereomer β:

LC-MS: calculated for C₁₇H₂₁N 239, observed m/e 240 (M+H)⁺ (2.0 min).

REFERENCE EXAMPLE 4

1-Amino-1,2,3-triphenylpropane p-toluenesulfonate salt

Diastereomer α:

LC-MS: calculated for C₂₁H₂₁N 287, observed m/e 288 (M+H)⁺ (2.3 min).

Diastereomer β:

LC-MS: calculated for C₂₁H₂₁N 287, observed m/e 288 (M+H)⁺ (2.3 min).

REFERENCE EXAMPLE 5

2-Amine-4-(4-chlorophenyl)-3-phenylbutane hydrochloride salt

Diastereomer α:

LC-MS: calculated for C₁₆H₁₈ClN 259, observed m/e 260 (M+H)⁺ (2.3 min).

Diastereomer β:

LC-MS: calculated for C₁₆H₁₈ClN 259, observed m/e 260 (M+H)⁺ (2.2 min).

REFERENCE EXAMPLE 6

2-Amino-3-(4-chlorophenyl)-4-phenylbutane hydrochloride salt

Diastereomer α:

LC-MS: calculated for C₁₆H₁₈ClN 259, observed m/e 260 (M+H)⁺ (2.3 min).

Diastereomer β:

LC-MS: calculated for C₁₆H₁₈ClN 259, observed m/e 260 (M+H)⁺ (2.1 min).

REFERENCE EXAMPLE 7

2-Amino-4-(4-methoxycarbonylphenyl)-3-phenylbutane hydrochloride salt

Diastereomer α:

LC-MS: calculated for C₁₈H₂₁NO₂ 283, observed m/e 284 (M+H)⁺ (2.0 min).

Diastereomer β:

LC-MS: calculated for C₁₈H₂₁NO₂ 283, observed m/e 284 (M+H)⁺ (1.9 min).

REFERENCE EXAMPLE 8

2-Amino-3-(2-Chlorophenyl)-4-phenylbutane (Mixture of Diastereomers α/β1:2)

LC-MS: calculated for C₁₆H₁₈ClN 259, observed m/e 260 (M+H)⁺ (1.9/2.0min).

REFERENCE EXAMPLE 9

2-Amino-3-(4-methoxyphenyl)-4-phenylbutane (Mixture of Diastereomers α/β2:5)

LC-MS: m/e 256 (M+H)⁺ (1.7 min).

REFERENCE EXAMPLE 10

N-[3-(4-Chlorophenyl)-2-phenyl-1-methylpropyl]-amine hydrochloride(Diastereomer α)

Step A 3-(4-Chlorophenyl)-2-phenylpropanoic acid, methyl ester.

To a solution of methyl phenylacetate (12 g, 80 mmol) and 4-chlorobenzylbromide (16 g, 80 mmol) in 250 mLanhydrous THF at −78° C. was addedsodium hexamethyldisilazide (1 M in THF, 80 mL, 80 mmol) (potassiumhexamethyldisilazide in toluene may be used with similar results). Thereaction was allowed to warm to room temperature overnight. The volatilematerials were removed on a rotary evaporator, and the resulting mixturewas partitioned between saturated ammonium chloride (200 mL) and EtOAc(200 mL). The organic layer was separated and the aqueous layerextracted with EtOAc (2×200 mL). The combined organic extracts weredried over anhydrous sodium sulfate, filtered, and concentrated todryness to give the title compound.

¹H NMR (500 MHz, CD₃OD): δ 7.36-7.10 (m, 9H), 3.81 (dd, 1H), 3.52 (s,3H), 3.36 (dd, 1H), 3.02 (dd, 1H).

Step B 3-(4-Chlorophenyl)-2-phenylpropanoic acid.

To a mixture of methyl 3-(4-chlorophenyl)-2-phenylpropionate (Step A, 20g, 74 mmol) in acetonitrile (100 mL) and water (100 mL) was addedlithium hydroxide monohydrate (8.8 g, 0.21 mol). After stirring at roomtemperature for 3 days, the volatile materials were removed byconcentrating on a rotary evaporator and the residue was partitionedbetween water (300 mL) and hexane/ether (1:1, 200 mL). The water layerwas separated, acidified to pH=2-3, and extracted with EtOAc (2×200 mL)The combined organic extracts were dried over anhydrous sodium sulfate,filtered, and concentrated to dryness to give the title compound. ¹H NMR(500 MHz, CD₃OD): δ 7.34-7.10 (m, 9H), 3.82 (dd, 1H), 3.36 (dd, 1H),2.98 (dd, 1H).

Step C N-Methoxy-N-methyl-3-(4-chlorophenyl)-2-phenylpropanamide.

To a solution of 3-(4-chlorophenyl)-2-phenylpropionic acid (Step B, 14g, 55 mmol) in CH₂Cl₂ (125 mL) at 0° C. was added dimethyl formamide (50μL) and oxalyl chloride (14 g, 0.11 mol) dropwise. The reaction wasallowed to warm to room temperature overnight and concentrated todryness to give the crude acyl chloride, which was used without furtherpurification. Thus, to a solution of the acyl chloride in CH₂Cl₂ (250mL) was added N-methoxy-N-methylamine hydrochloride (11 g, 0.11 mol) andtriethyl amine (dried over activated molecular sieves, 30 mL, 0.22 mol)at 0° C. After stirring at room temperature for 4 h, the reactionmixture was diluted with ether (500 mL) and successively washed withwater, dilute aqueous sodium hydrogen sulfate and brine, dried overanhydrous MgSO₄, filtered, and concentrated to dryness to give the crudeproduct, which was used without further purification. ¹H NMR (500 MHz,CD₃OD): δ 7.4-7.1 (m, 9H), 4.38 (br, 1H), 3.48 (s, 3H), 3.35 (dd, 1H),3.10 (s, 3H), 2.92 (dd, 1H); LC-MS: m/e 304 (3.6 min).

Step D 4-(4-Chlorophenyl)-3-phenyl-2-butanone.

To a solution ofN-methoxy-N-methyl-3-(4-chlorophenyl)-2-phenylpropanamide (Step C, 16 g,53 mmol, dried by azeotroping with toluene) in anhydrous THF (200 mL) at0° C. was added methylmagnesium bromide (3 M in ether, 35 mL, 0.11 mol).After stirring at 0° C. for 2 h, the reaction was quenched with MeOH (5mL) and 2 M hydrochloric acid (50 mL). The volatile materials wereremoved by concentrating on a rotary evaporator and the residuepartitioned between saturated ammonium chloride (200 mL) and ether (200mL). The organic layer was separated, and the aqueous layer wasextracted with ether (2×200 mL). The combined organic extracts weredried over anhydrous MgSO₄, filtered and concentrated to dryness to givethe title compoun, which was used without further purification. ¹H NMR(500 MHz, CD₃OD): δ 7.45-7.02 (m, 9H), 4.08 (dd, 1H), 3.34 (dd, 1H),2.90 (dd, 1H), 2.03 (s, 3H).

Step E 4-(4-Chlorophenyl)-3-phenyl-2-butanol.

To a solution of 4-(4-chlorophenyl)-3-phenyl-2-butanone (Step D, 13 g,50 mmol) in MeOH (100 mL) at 0° C. was added sodium borohydride (3.8 g,100 mmol). After stirring at 0° C. for 30 min, the reaction was quenchedby addition of 2 M hydrochloric acid (50 mL). The volatile materialswere removed by concentrating on a rotary evaporator and the residuepartitioned between water (100 mL) and EtOAc (200 mL). The organic layerwas separated and the aqueous layer extracted with EtOAc (2×200 mL). Thecombined organic extracts were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated to dryness to give the crudeproduct, which was purified by flash column chromatography on silica geleluted with 10% EtOAc in hexane to afford the pure faster eluting isomerand a mixture containing both the faster eluting isomer and the slowereluting isomer. Faster eluting isomer: ¹H NMR (500 MHz, CD₃OD): δ7.25-7.00 (m, 9H), 4.00 (m, 1H), 3.15 (m, 1H), 2.97 (m, 1H), 2.85 (m,1H), 1.10 (d, 3H).

Step F 4-(4-Chlorophenyl)-2-methanesulfonyloxy-3-phenylbutane.

To a solution of 4-(4-chlorophenyl)-3-phenyl-2-butanol (Step E, fastereluting isomer, 9.0 g, 34 mmol) in EtOAc (100 mL) at 0° C. was addedtriethyl amine (dried over activated molecular sieves, 5.8 mL. 42 mmol)and methanesulfonyl chloride (3.0 mL, 38 mmol). After stirring at 0° C.for 30 min, the reaction was quenched by addition of saturated aqueoussodium bicarbonate (100 mL). After stirring at room temperature for 1 h,the organic layer was separated, dried over anhydrous sodium sulfate,filtered, and concentrated to dryness to give the title compound, whichwas used without further purification. ¹H NMR (500 MHz, CD₃OD): δ7.3-7.0 (m, 9H), 5.05 (m, 1H), 3.2-3.0 (m, 3H), 2.80 (s, 3H), 1.40 (d,3H).

Step G 2-Azido-4-(4-chlorophenyl)-3-phenylbutane.

To a solution of 4-(4-chlorophenyl)-2-methanesulfonyloxy-3-phenylbutane(Step F, 12 g, 34 mmol) in DMF (50 mL) was added sodium azide (11 g,0.17 mol). After stirring at 120° C. for 1 h, the reaction mixture waspoured into water (200 mL), and the product was extracted with ether(2×100 mL). The combined organic extracts were washed with water, driedover MgSO₄, filtered and concentrated to dryness, and the residue waspurified on a silica gel column eluting with hexane to give the titlecompound.

Step H 2-(N-tert-Butoxycarbonyl)amino-4-(4-chlorophenyl)-3-phenylbutane

To a solution of 2-azido-4-(4-chlorophenyl)-3-phenylbutane (Step G, 7.0g, 24 mmol) in EtOAc (150 mL) was added di(tert-butyl) dicarbonate (8.0g, 37 mmol) and platinum dioxide (0.50 g, 2.2 mmol). The mixture wasdegassed and filled with hydrogen with a balloon. After stirring for 1day, the reaction mixture was filtered through CELITE diatomaceousearth, and the filtrate was concentrated to give the crude product,which was contaminated with some unreacted di(tert-butyl) dicarbonate.¹H NMR (500 MHz, CD₃OD): δ 7.25-6.88 (m, 9H), 3.89 (m, 1H), 3.20 (m,1H), 2.86-2.77 (m, 2H), 1.54 (s, 9H), 0.92 (d, 3H).

Step I N-[3-(4-Chlorophenyl)-2-phenyl-1-methylpropyl]-aminehydrochloride (Diastereomer α).

2-(N-tert-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-phenylbutane (StepH, 7.0 g, 24 mmol) was treated with a saturated solution of hydrogenchloride in EtOAc (100 mL) at room temperature for 30 min (4 M hydrogenchloride in dioxane may be used with similar results). The mixture wasconcentrated to dryness to give the title compound. ¹H NMR (500 MHz,CD₃OD): δ 7.35-6.98 (m, 9H), 3.62 (m, 1H), 3.20 (dd, 1H), 3.05 (m, 1H),2.98 (dd, 1H), 1.19 (d, 3H). LC-MS: m/e 260 (M+H)⁺ (2.3 min).

REFERENCE EXAMPLE 11

N-[3-(4-Chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine hydrochloride

Step A 4-(4-Chlorophenyl)-3(S)-phenyl-2(R)-butanol.

A sample of magnesium (20 g, 0.82 mol) was activated by stirring undernitrogen for 12 h, and anhydrous ether (100 mL) was added to cover thesolid material. The mixture was cooled to 0° C., and was added4-chlorobenzyl chloride (40 g, 0.25 mmol) in 400 mL anhydrous etherdropwise. After stirring at room temperature for 1 h, a sample of theabove solution (32 mL) was added to (1R,2R)-1-phenylpropylene oxide (1.0g, 7.5 mmol) in 100 mL ether at 0° C. via syringe. After stirring at 0°C. for 2 h, the reaction was quenched by addition of saturated aqueousammonium chloride (100 mL). The organic layer was separated and theaqueous layer extracted with ether (2×100 mL). The combined organicextracts were washed with brine, dried over anhydrous MgSO₄, filtered,and concentrated to dryness, and the residue was purified by flashcolumn chromatography on silica gel eluted with hexane to 15% EtOAc inhexane to afford the title compound. ¹H NMR (500 MHz, CD₃OD): δ7.28-7.02 (m, 9H), 4.01 (m, 1H), 3.14 (dd, 1H), 2.97 (dd, 1H), 2.85 (m,1H), 1.12 (d, 3H).

Step B N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine,hydrochloride

The product of Step A (4-(4-chlorophenyl)-3(S)-phenyl-2(R)-butanol, 1.8g, 7.0 mmol) was converted to the title compound following the stepsdescribed in Reference Example 10, Steps F-I, except hydrogen chloridein dioxane (4 M) was used in place of hydrogen chloride in EtOAc. ¹H NMR(500 MHz, CD₃OD): δ 7.35-6.98 (m, 9H), 3.62 (m, 1H), 3.20 (dd, 1H), 3.05(m, 1H), 2.98 (dd, 1H), 1.19 (d, 3H). LC-MS: m/e 260 (M+H)⁺ (2.3 min).

REFERENCE EXAMPLE 12

2-Amino-4-(4-chlorophenyl)-3-(3-fluorophenyl)butane hydrochloride salt(Mixture of Diastereomers α/β 5:1)

Step A Methyl 3-(4-Chlorophenyl)-2-(3-fluorophenyl)propionate

To a solution of 3-fluorophenylacetic acid (5.0 g, 32 mmol) in MeOH (25mL) and CH₂Cl₂ (25 mL) at 0° C. was added trimethylsilyldiazomethane (2M in hexane, 30 mL, 60 mmol). After stirring at room temperature for 15min, the reaction mixture was concentrated to dryness, and the residuewas azeotroped with toluene to give the crude methyl3-fluorophenylacetate (5.6 g), which was used without furtherpurification. Thus, the crude methyl 3-fluorophenylacetate obtainedabove (2.5 g, 15 mmol) was converted to the title compound (purified onsilica gel) by reacting with 4-chlorobenzyl bromide (4.6 g, 22 mmol) andsodium hexamethyldisilazide (1 M in THF, 15 mL, 15 mmol) following theprocedure described in Reference Example 10, Step A. ¹H NMR (400 MHz,CD₃OD): δ 7.35-6.88 (m, 8H), 3.92 (t, 1H), 3.60 (s, 3H), 3.34 (dd, 1H),3.00 (dd, 1H). LC-MS: m/e 305 (M+Na)⁺ (3.9 min).

Step B N-Methoxy-N-methyl-3-(4-chlorophenyl)-2-(3-fluororophenyl)propanamide.

To a suspension N-methoxy-N-methylamine hydrochloride (2.0 g, 21 mmol)in 50 mL CH₂Cl₂ at 0° C. was added dimethylaluminum chloride (1 M inhexane, 21 mL, 21 mmol). After stirring at room temperature for 1 h, asolution of methyl 3-(4-chlorophenyl)-2-(3-flurophenyl)propionate (StepA, 2.0 g, 10 mmol) in CH₂Cl₂ (10 mL) was added, and the resultingmixture was stirred overnight. The reaction mixture was quenched byaddition of MeOH (5 mL), and the resulting mixture was concentrated withsilica gel (50 g). The material was loaded onto a silica gel column,which was eluted with 10% EtOAc in hexane to 2% ammonia in MeOH (2 M) in10% EtOAc/hexane to give the title compound. ¹H NMR (400 MHz, CD₃OD): δ7.35-6.90 (m, 8H), 4.39 (br, 1H), 3.41 (s, 3H), 3.38-3.30 (m, 1H), 3.08(s, 3H), 2.92 (dd, 1H). LC-MS: m/e 322 (M+H)⁺ (3.6 min).

Step C 4-(4-Chlorophenyl)-3-(3-fluorophenyl)-2-butanol

The product of Step B(N-methoxy-N-methyl-3-(4-chlorophenyl)-2-phenylpropionamide) (0.74 g,2.3 mmol) was converted to the title compound (a 5:1 mixture ofdiastereomers) following the procedure described in Reference Example10, Steps D-E. ¹H NMR (400 MHz, CD₃OD): δ 7.22-6.78 (m, 8H), 3.98 (m,1H), 3.11 (dd, 1H), 2.94 (dd, 1H), 2.85 (m, 1H), 1.08 (d, 3H).

Step D 2-Azido-4-(4-chlorophenyl)-3-(3-fluorophenyl)butane.

To a mixture of 4-(4-chlorophenyl)-2-(3-fluorophenyl)-2-butanol (Step C,0.65 g, 2.3 mmol), triphenylphosphine (1.2 g, 4.7 mmol), imidazole (0.32g, 4.7 mmol) and zinc azide dipyridine complex (Viaud, M. C.; Rollin, P.Synthesis 1990, 130) (0.72 g, 2.3 mmol) in 10 mL CH₂Cl₂ was addeddiethylazodicarboxylate (0.73 mL, 4.7 mmol) at 0° C. After stirring atroom temperature for 30 min, the resulting mixture was concentrated withsilica gel (20 g) and loaded onto a silica gel column, which was elutedwith 2% ether in hexane to 2% ammonia in MeOH (2 M) in 2% ether/hexaneto give the title compound. ¹H NMR (400 MHz, CD₃OD): δ 7.25-6.85 (m,8H), 3.76 (m, 1H), 3.33 (m, 1H), 2.92 (m, 2H), 1.15 (d, 3H).

Step E 2-Amino-4-(4-Chlorophenyl)-3-(3-fluorophenyl)butane hydrochloridesalt (Mixture of Diastereomers α/β 5:1)

The product of Step D(2-azido-4-(4-chlorophenyl)-3-(3-fluorophenyl)butane) (0.49 g, 1.6 mmol)was converted to the title compound following the steps described inReference Example 10, Steps H-I. ¹N NMR (400 MHz, CD₃OD): δ 7.32-6.90(m, 7H), 3.61 (m, 1H), 3.20 (dd, 1H), 3.11 (m, 1H), 2.92 (dd, 1H), 1.19(d, 3H). LC-MS: m/e 278 (M+H)⁺ (2.4 min).

The amines of Reference Examples 13-16 were prepared according to theprocedures described in Reference Example 12:

REFERENCE EXAMPLE 13

2-Amino-4-(4-chlorophenyl)-3-(2-fluorophenyl)butane hydrochloride salt(Mixture of Diastereomers α/β 10:1)

LC-MS: m/e 278 (M+H)⁺ (2.3 min).

REFERENCE EXAMPLE 14

2-Amino-4-(4-chlorophenyl)-3-(4-fluorophenyl)butane hydrochloride salt(Mixture of Diastereomers α/β 10:1)

LC-MS: m/e 278 (M+H)⁺ (2.5 min).

REFERENCE EXAMPLE 15

2-Amino-4-(4-chlorophenyl)-3-(2-pyridyl)butane hydrochloride salt(Mixture of Diastereomers α/β 10:1)

LC-MS: m/e 261 (M+H)⁺ (1.6 min).

REFERENCE EXAMPLE 16

2-Amino-4-(4-chlorophenyl)-3-(4-pyridyl)butane hydrochloride salt(Mixture of Diastereomers α/β 10:1)

Trimethyl aluminum was used in place of dimethylaluminum chloride atStep B of Reference Example 12. LC-MS: m/e 261 (M+H)⁺.

REFERENCE EXAMPLE 17

2-Amino-4-(4-cyanophenyl)-3-phenylbutane hydrochloride salt (Mixture ofDiastereomers α/β 10:1)

Step A 4-(4-Cyanophenyl)-3-phenyl-2-butanone

To a solution of phenylacetone (1.2 g, 9.0 mmol) and 4-cyanobenzylchloride (1.4 g, 9.0 mmol) in 20 mL CH₂Cl₂ at −78° C. was added cesiumhydroxide monohydrate (4.5 g, 27 mmol) and tetrabutyl ammonium iodide(20 mg). The reaction was allowed to warm to room temperature over 6 h,and the resulting mixture partitioned between brine (100 mL) and EtOAc(100 mL). The organic layer was separated and the aqueous layerextracted with EtOAc (2×100 mL). The combined organic extracts weredried over MgSO₄, filtered, and concentrated to dryness, and the residuewas purified by flash column chromatography on silica gel eluted with20-50% EtOAc in hexane to give the title compound. ¹H NMR (500 MHz,CD₃OD): δ 7.52 (d, 2H), 7.34-7.16 (m, 7H), 4.12 (dd, 1H), 3.41 (dd, 1H),3.00 (dd, 1H). LC-MS: m/e 250 (M+H)⁺ (3.2 min).

Step B 2-Amine-4-(3-cyanophenyl)-3-phenylbutane hydrochloride salt(Mixture of Diastereomers α/β 10:1).

The product of Step A (4-(4-cyanophenyl)-3-phenyl-2-butanone) (1.0 g,4.0 mmol) was converted to the title compound following the proceduredescribed in Reference Example 10, Steps E-I. LC-MS: m/e 251 (M+H)⁺ (1.9min).

REFERENCE EXAMPLE 18

2-Amino-4-(5-chloro-2-pyridyl)-3-phenylbutane hydrochloride salt(Mixture of Diastereomers α/β 10:1)

5-Chloro-2-choromethylpyridine (Weidmann, K. et al. J. Med. Chem. 1992,35, 438) was used in place of 4-cyanobenzyl bromide in Step A ofReference Example 17. LC-MS: m/e 261 (M+H)⁺.

REFERENCE EXAMPLE 19

N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-amine, hydrochloride(Mixture of Diastereomers α/β 10:1)

Step A 4-(4-Chlorophenyl)-3-pyridyl-2-butanone.

To a solution of 3-pyridylacetone hydrochloride (Wibaud, van der V.Recl. Trav. Chim. Pays-Bas. 1952, 71, 798) (10 g, 58 mmol) and4-chlorobenzyl chloride (9.1 g, 58 mmol) in 100 mL CH₂Cl₂ at −78° C. wasadded cesium hydroxide monohydrate (39 g, 0.23 mol) and tetrabutylammonium iodide (1 g). The reaction was allowed to warm to roomtemperature overnight, and the resulting mixture was partitioned betweenbrine (100 mL) and EtOAc (100 mL). The organic layer was separated andthe aqueous layer extracted with EtOAc (2×100 mL). The combined organicextracts were dried over anhydrous MgSO₄, filtered, and concentrated todryness to give the title compound. ¹H NMR (500 MHz, CD₃OD): δ 8.42 (d,1H), 8.34 (d, 1H), 7.72 (d, 1H), 7.40 (dd, 1H), 7.18 (d, 2H), 7.06 (d,1H), 4.23 (dd, 1H), 3.38 (dd, 1H), 2.95 (dd, 1H), 2.10 (s, 3H). LC-MS:m/e 260 (M+H)⁺ (1.9 min).

Step B N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-amine,hydrochloride (Mixture of Diastereomers α/β 10:1).

The product of Step A (4-(4-chlorophenyl)-3-pyridyl-2-butanone) (14 g,57 mmol) was converted to the title compound following the proceduredescribed in Reference Example 10, Steps E-I. LC-MS: m/e 261 (M+H)⁺ (1.2min).

REFERENCE EXAMPLE 20

2-Amino-4-(2,4-dichlorophenyl)-3-(4-chlorophenyl)butane hydrochloridesalt (3 Isomers)

Step A Methyl 3-(2,4-Dichlorophenyl)-2-(4-chorophenyl)propionate.

A sample of 4-chlorophenylacetic acid (4.2 g, 25 mmol) was converted tothe title compound (6.5 g) following the procedure in Reference Example12, Step A substituting 4-chlorophenylacetic acid for3-fluorophenylacetic acid and 2,4-dichlorobenzyl bromide for4-chlorobenzyl bromide following the procedures described in ReferenceExample 10, Step A. ¹H NMR (500 MHz, CD₃OD): δ 7.40 (d, 1H), 7.32-7.22(m, 4 H), 7.15 (dd, 1H), 7.08 (d, 1H), 4.00 (t, 1H), 3.62 (s, 3H), 3.44(dd, 1H), 3.12 (dd, 1H).

Step B 3-(2,4-Dichlorophenyl)-2-(4-chlorphenyl)propanol.

To a solution of methyl 3-(2,4-dichlorophenyl)-2-(4-chorophenyl)propionate (6.4 g, 8.6 mmol) in 50 mL ether at −40° C. was added lithiumaluminum hydride (1.4 g, 37 mmol), and the reaction was allowed to warmto room temperature over 2 h. The reaction was quenched by addition ofMeOH (3 mL) dropwise at −10° C., and the mixture was partitioned between100 mL saturated ammonium chloride and EtOAc (100 mL). The organic layerwas separated and the aqueous layer extracted with EtOAc (2×100 mL). Thecombined organic extracts were dried over anhydrous MgSO₄, filtered, andconcentrated to dryness to give the title compound, which was usedwithout further purification. ¹H NMR (400 MHz, CD₃OD): δ 7.4-6.9 (m,7H), 3.72 (m, 2H), 3.24 (dd, 1H), 3.16 (m, 1H), 2.85 (dd, 1H).

Step C 3-(2,4-Dichlorophenyl)-2-(4-chorophenyl)propanal.

To a solution of 3-(2,4-dichlorophenyl)-2-(4-chorophenyl)propanol (StepB, 0.89 g, 2.8 mmol) in 20 mL CH₂Cl₂ was added crushed activatedmolecular sieves (4 g). After stirring at room temperature for 10 min,pyridinium chlorochromate (0.90 g, 4.2 mmol) was added. After stirringat room temperature for 1 h, CELITE diatomaceous earth (4 g) was addedfollowed by 100 mL ether. The resulting mixture was filtered through asilica gel pad, which was washed with ether (2×50 mL). The filtrate wasconcentrated to dryness and azeotroped with toluene to give the titlecompound, which was used without further purification.

Step DN-[3-(2,4-Dichlorophenyl)-2-(4-chorophenyl)propylidene]-2-methylpropanesulfinamde.

To a solution of 3-(2,4-dichlorophenyl)-2-(4-chorophenyl)propanal (StepC, 0.90 g, 2.8 mmol) in 6 mL THF was added(R)-(+)-2-methyl-2-propane-sulfinamide (0.5 gm, 4.1 mmol) followed bythe addition of titanium tetraethoxide (1.5 mL, 8.0 mmol). Afterstirring at room temperature overnight, the reaction mixture was addedto a well-stirred brine solution (50 mL). The resulting mixture wasfiltered through CELITE diatomaceous earth and washed with EtOAc (20mL), and the filtrate was extracted with EtOAc (2×50 mL). The combinedextracts were dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness, and the residue was purified by flash columnchromatography on silica gel eluted with 10% ether in hexane to give thetitle compound as a 1:1 mixture of diastereomers. ¹H NMR (500 MHz,CD₃OD): δ 8.11 (m, 1H), 7.41 (m, 1H), 7.35-7.31 (m, 4 H), 7.16-7.06 (m,2H), 4.26 (m, 1H), 3.78-3.58 (m, 1H), 3.22-3.14 (m, 1H), 1.13/1.12 (s,9H).

Step EN-[3-(2,4-Dichlorophenyl)-2-(4-chorophenyl)-1-methylpropyl]-2-methylpropanesulfinamide(3 Isomers)

To a solution ofN-[3-(2,4-dichlorophenyl)-2-(4-chorophenyl)-1-methylpropylidene]-2-methylpropanesulfinamde(Step D, 0.51 g, 1.3 mmol) in 6 mL CH₂Cl₂at −60° C. was addedmethylmagnesium bromide (3 M in ether, 0.90 mL, 2.7 mmol). Afterstirring at −60° C. for 6 h, the reaction was allowed to warm to roomtemperature overnight. The resulting mixture was partitioned betweensaturated aqueous ammonium chloride (50 mL) and EtOAc (50 mL). Theorganic layer was separated and the aqueous layer extracted with EtOAc(2×50 mL). The combined extracts were dried over anhydrous sodiumsulfate, filtered, and concentrated to dryness, and the residue waspurified by flash column chromatography on silica gel eluted with 30 to50% EtOAc in hexane to give the title compound as one pure fastereluting enantiomer and a 1:1 mixture of slower co-eluting diastereomers.The addition of the methyl Grignard reagent was apparentlystereoselective for one of the sulfinamide diastereomers.

Faster eluting isomer: ¹H NMR (500 MHz, CD₃OD): δ 7.30 (d, 1H), 7.22 (d,2H), 7.12 (d, 2H), 7.03 (dd, 1H), 6.94 (d, 1H), 3.62 (m, 1H), 3.56 (dd,1H), 2.97 (dd, 1H), 1.23 (s, 9H), 1.04 (d, 3H). LC-MS: m/e 432 (M+H)⁺(4.2 min). Slower eluting isomers (1:1): ¹H NMR (500 MHz, CD₃OD): δ7.33/7.30 (d, 1H), 7.21/7.18 (d, 2H), 7.06/7.04 (d, 2H), 6.99/6.97 (dd,1H), 6.79/6.75 (d, 1H), 3.70-3.55 (m, 1H), 3.07/2.97 (m, 1H), 2.90/2.80(dd, 1H), 1.32/0.95 (s, 9H), 1.49/1.10 (d, 3H).Step F 2-Amino-4-(2,4-dichlorophenyl)-3-(4-chorophenyl)butanehydrochloride (3 Isomers).

To a solution ofN-[3-(2,4-dichlorophenyl)-2-(4-chorophenyl)-1-methylpropyl]-2-methylpropanesulfinamde(Step F, faster eluting isomer, 50 mg, 0.11 mmol) in 5 mL MeOH was addedhydrogen chloride in dioxane (4 M, 2 mL). After stirring at roomtemperature for 10 min, the reaction mixture was concentrated to drynessto give the title compound as one pure isomer.

Isomer 1: ¹H NMR (500 MHz, CD₃OD): δ 7.35 (d, 1H), 7.29 (d, 2H), 7.15(d, 2H), 7.06 (dd, 1H), 6.91 (d, 1H), 3.68 (m, 1H), 3.36 (dd, 1H), 3.06(dd, 1H), 1.18 (d, 3H). LC-MS: m/e 328 (M+H)⁺ (2.8 min).

The two slower co-eluting isomers were treated in the same fashion togive two other isomers of the title compound. Isomer 2 and 3 (1:1):LC-MS: m/e 328 (M+H)⁺ (2.7/2.8 min).

REFERENCE EXAMPLE 21

2-Amino-4-(4-chloro-2-fluorophenyl)-3-(4-chlorophenyl)butanehydrochloride salt (Isomers, 1, 2 and 3)

The title compound was prepared according to the procedures of ReferenceExample 20 substituting 2,5-dichlorobenzyl bromide with4-chloro-2-fluorobenzyl bromide.

Isomer 1: LC-MS: m/e 312 (M+H)⁺ (2.6 min). Isomer 2 and 3 (1:1): LC-MS:m/e 312 (M+H)⁺ (2.5/2.6 min).

REFERENCE EXAMPLE 22

2-(4-Chlorophenyloxy)-2-(4-chlorophenyl)ethylamine hydrochloride salt

Step A 2-(4-Chlorophenyloxy)-2-(4-chlorophenyl)ethanol.

To a suspension of 2-(4-chlorophenyloxy)-2-(4-chlorophenyl)acetic acid(Newman et al J. Amer. Chem. Soc. 1947, 69, 718) (1.0 g, 3.4 mmol) in 10mL THF at 0° C. was added borane (1 M in THF, 6.8 mL, 6.8 mmol). Afterstirring at room temperature for 2 h, the reaction was quenched byaddition of 2 M hydrochloric acid (10 mL). The volatile materials wereremoved on a rotary evaporator, and the resulting mixture waspartitioned between brine (20 mL) and EtOAc (30 mL). The organic layerwas separated and the aqueous layer extracted with EtOAc (2×20 mL). Thecombined extracts were dried over anhydrous sodium sulfate, filtered,and concentrated to dryness to give the title compound, which was usedwithout further purification. LC-MS: m/e 283 (M+H)⁺ (3.4 min).

Step B 2-(4-Chlorophenoylxy)-2-(4-chlorophenyl)ethyl Azide

2-(4-Chlorophenyloxy)-2-(4-chlorophenyl)ethanol (Step A, 0.45 g, 2.4mmol) was converted to the title compound (0.29 g) following theprocedure described in Reference Example 12, Step D. ¹H NMR (500 MHz,CD₃OD): δ 7.41 (d, 2H), 7.37 (d, 2H), 7.18 (d, 2H), 6.86 (d, 2H), 5.42(dd, 1H), 3.69 (dd, 1H), 3.45 (dd, 1H). LC-MS: m/e 308 (M+H)⁺ (4.3 min).

Step C 2-(4-Chlorophenoylxy)-2-(4-chlorophenyl)ethylamine.

To a solution of 2-(4-chlorophenoylxy)-2-(4-chlorophenyl)ethyl azide(Step B, 0.23 g, 0.75 mmol) in 4 mL THF at −20° C. was addedtrimethylphosphine (0.18 mL, 1.8 mmol), and the reaction was allowed towarm to room temperature over 2 h. Lithium hydroxide monohydrate (61 mg,1.5 mmol) was added followed by 2 mL water. After stirring at roomtemperature for 30 min, the reaction was quenched by addition of 2 Mhydrochloric acid (final pH=2). The volatile materials were removed on arotary evaporator, and the resulting mixture was partitioned betweenbrine (20 mL), 5 N aqueous sodium hydroxide (20 mL), ether (20 mL) andtoluene (20 mL). The organic layer was separated and the aqueous layerextracted with ether (40 mL). The combined extracts were dried overanhydrous MgSO₄, filtered, and concentrated to dryness to give the titlecompound (0.43 g), which was contaminated with trimethylphosphine oxideand was used without further purification. ¹H NMR (500 MHz, CD₃OD): δ7.46-7.40 (m, 4H), 7.20 (d, 2H), 6.91 (d, 2H), 5.53 (m, 2H), 3.36 (m,2H). LC-MS: m/e 282 (M+H)⁺ (2.5 min).

REFERENCE EXAMPLE 23

2,2-Bis(4-chlorophenyl)ethylamine hydrochloride salt

Step A Methyl 3,3-Bis(4-chlorophenyl)propenoate

A mixture of di(4-chlorophenyl)ketone (7.5 g, 30 mmol) and methyl(triphenylphosphoranylidene)acetate (10 g, 30 mmol) in 20 mL toluene washeated at 130° C. while allowing the solvent to slowly evaporateovernight. The resulting mixture was dissolved in CH₂Cl₂ (20 mL) andtoluene (20 mL) and was concentrated with 30 g silica gel. The materialwas loaded onto a silica gel column, which was eluted with 6:3:1hexane/CH₂Cl₂/ether to give the title compound.

Step B Methyl 3,3-Bis(4-chlorophenyl)propionate

A suspension of methyl 3,3-bis(4-chlorophenyl)propenoate (Step A, 3.0 g,14 mmol) and platinum dioxide (0.30 g) in MeOH (20 mL) and 2 M aqueoushydrochloric acid (1 mL) was degassed and filled with hydrogen with aballoon. After stirring at room temperature for 2 h, the reactionmixture was filtered through CELITE diatomaceous earth, and the filtratewas concentrated to dryness. The residue was dissolved in 50 mL etherand was concentrated with 20 g silica gel. The material was loaded ontoa silica gel column, which was eluted with 10% ether in hexane to givethe title compound. ¹H NMR (500 MHz, CD₃OD): δ 7.29-7.22 (m, 4H), 4.50(t, 1H), 3.56 (s, 3H), 3.07 (d, 2H). LC-MS: m/e 309 (M+H)⁺ (4.1 min).

Step C 3,3-Bis(4-chlorophenyl)propionic Acid

A mixture of methyl 3,3-bis(4-chlorophenyl)propionate (Step B, 0.78 g,3.9 mmol), lithium hydroxide monohydrate (0.33 g, 7.8 mmol) in 1:1:1MeOH/THF/water (15 mL) was stirred at room temperature overnight. Theresulting mixture was partitioned between 2 M aqueous hydrochloric acid(50 mL) and ether (50 mL). The organic layer was separated and theaqueous layer extracted with EtOAc (2×50 mL). The combined extracts weredried over anhydrous MgSO₄, filtered, and concentrated to dryness togive the title compound. ¹H NMR (500 MHz, CD₃OD): δ 7.29-7.23 (m, 4H),4.49 (t, 1H), 3.02 (d, 2H).

Step D N-[2,2-Bis(4-chlorophenyl)ethyl]allylcarbamate.

To a solution of 3,3-bis(4-chlorophenyl)propionic acid (Step C, 0.32 g,1.1 mmol) and triethyl amine (0.60 mL, 4.3 mmol) in 4 mL THF at 0° C.was added ethyl chloroformate (0.31 mL, 3.3 mmol). After stirring atroom temperature for 30 min, the reaction was cooled to 0° C., and wasadded sodium azide (0.35 g, 5.4 mmol) in 2 mL water. After stirring atroom temperature for 1 h, the reaction mixture was partitioned betweenbrine (20 mL) and EtOAc (20 mL). The organic layer was separated and theaqueous layer extracted with EtOAc (2×20 mL). The combined extracts weredried over anhydrous sodium sulfate, filtered, and concentrated todryness, and the residue was dissolved in allylic alcohol (1 mL) andtoluene (1 mL). After stirring at 80° C. overnight, the reaction mixturewas concentrated to dryness, and the residue was purified by flashcolumn chromatography on silica gel column eluted with 20% EtOAc inhexane to give the title compound. ¹H NMR (500 MHz, CD₃OD): δ 7.30-7.21(m, 4H), 5.84 (m, 1H), 5.17 (dd, 1H), 5.10 (dd, 1H), 4.46 (d, 2H), 4.22(t, 1H), 3.68 (d, 2H). LC-MS: m/e 350 (M+H)⁺ (3.9 min).

Step E 2,2-Bis(4-chlorophenyl)ethylamine hydrochloride salt.

To a solution of N-[2,2-bis(4-chlorophenyl)ethyl]allylcarbamate (Step D,0.26 g, 0.73 mmol) in 1.5 mL THF at 0° C. was added tetrakis(triphenylphosphine)palladium (85 mg, 0.073 mmol) and triphenylsilane(0.18 mL, 1.1 mmol). After stirring at 0° C. for 1 h, the reactionmixture was partitioned between ether (20 mL) and 2 M hydrochloric acid(20 mL). The aqueous layer was separated, and was added 5 N aqueoussodium hydroxide (final pH>12). The product was extracted with ether(3×30 mL), and the combined extracts were dried over sodium hydroxide,and filtered through CELITE, diatomaceous earth. After addition of 4 Mhydrogen chloride in dioxane (2 mL), the filtrate was concentrated todryness to give the title compound. ¹H NMR (500 MHz, CD₃OD): δ 7.40-7.34(m, 4H), 4.28 (m, 1H), 3.62 (d, 2H). LC-MS: m/e 266 (M+H)⁺ (2.3 min).

REFERENCE EXAMPLE 24

2-Amino-3-(4-chlorophenylthio)-3-(4-chlorophenyl)propane hydrochloridesalt (Two Diastereomers)

Step A Methyl 2-(4-Chlorophenylthio)-2-(4-chlorophenyl)acetate.

To a solution of 2-(4-chlorophenylthio)-2-(4-chlorophenyl)acetic acid(Nicolaescu et al Rev. Roum. Chim. 1979, 24, 137) (1.0 g, 3.0 mmol) inMeOH (10 mL) and CH₂Cl₂ (10 mL) at 0° C. was addedtrimethylsilyldiazomethane (2 M in hexane) until a yellow colorpersisted. Concentration afforded the title compound, which was usedwithout further purification.

Step B 2-Amino-3-(4-chlorophenylthio)-3-(4-chlorophenyl)propanehydrochloride salt (Two Diastereomers)

The product of Step A (methyl2-(4-chlorophenylthio)-2-(4-chlorophenyl)acetate) (1.1 g, 3.0 mmol) wasconverted to the title compound following the procedures described inReference Example 12, Steps B-E.

LC-MS: m/e 312 (M+H)⁺ (2.7 min).

REFERENCE EXAMPLE 25

2-Amino-3,4-bis(4-chlorophenyl)-2-methylbutane hydrochloride salt

Step A Methyl 2,3-Bis(4-chlorophenyl)propionate.

The title compound was prepared following the procedure described inReference Example 10, Step A, substituting methyl phenylacetate withmethyl 4-chlorophenylacetate. ¹H NMR (500 MHz, CD₃OD): δ 7.30-7.22 (m,4H), 7.19 (d, 2H), 7.09 (d, 2H), 3.90 (t, 1H), 3.58 (s, 3H), 3.32 (dd,1H), 2.98 (dd, 1H).

Step B 3,4-Bis(4-chlorophenyl)-2-methyl-2-butanol.

To a solution of methyl 2,3-bis(4-chlorophenyl)propionate (2.6 g, 8.4mmol) in ether (20 mL) was added methylmagnesium bromide (3 M in ether,8.4 mL, 25 mmol) at −10° C., and the reaction was allowed to warm toroom temperature over 2 h. The reaction mixture was poured intosaturated aqueous ammonium chloride (100 mL), and the product wasextracted with EtOAc (3×100 mL). The combined extracts were dried overanhydrous MgSO₄, filtered, and concentrated to dryness to give the titlecompound, which was used without further purification. ¹H NMR (500 MHz,CD₃OD): δ 7.17 (ABq, 4H), 7.06 (d, 2H), 6.93 (d, 2H), 3.32 (dd, 1H),2.94 (dd, 1H), 2.84 (dd, 1H), 1.20 (s, 3H), 1.16 (s, 3H).

Step C N-[2,3-Bis(4-chlorophenyl)-1,1-dimethylpropyl]chloroacetamide.

To a solution of 3,4-bis(4-chlorophenyl)-2-methyl-2-butanol (Step B, 1.4g, 4.5 mmol) and chloroacetonitrile (0.57 mL, 9.1 mmol) in acetic acid(0.7 mL) at −10° C. was added concentrated sulfuric acid (0.31 mL, 14mmol). After stirring at −10° C. for 15 min and room temperature for 2h, the reaction mixture was poured onto ice (20 g), and the product wasextracted with EtOAc (3×20 mL). The combined extracts were washed withbrine/saturated aqueous sodium bicarbonate, dried over anhydrous MgSO₄,filtered, and concentrated to dryness to give the title compound.

¹H NMR (500 MHz, CD₃OD): δ 7.19 (ABq, 4H), 7.06 (d, 2H), 6.95 (d, 2H),3.93 (ABq, 2H), 3.89 (dd, 1H), 3.10 (dd, 1H), 2.99 (dd, 1H), 1.43 (s,3H), 1.25 (s, 3H). LC-MS: m/e 384 (M+H)⁺ (3.9 min).

Step D 2-Amino-3,4-bis(4-chlorophenyl)-2-methylbutane hydrochloride

To a solution ofN-[2,3-bis(4-chlorophenyl)-1,1-dimethylpropyl]chloroacetamide (Step C,1.3 g, 3.8 mmol) in ethanol (10 mL) and acetic acid (2 mL) was addedthiourea (0.34 g, 4.5 mmol). The reaction was stirred at 80° C.overnight to give a white precipitate. The precipitate was removed byfiltration and washed with ethanol (10 mL), and the filtrate was dilutedwith dilute aqueous sodium hydroxide and extracted with hexane (2×50mL). The combined extracts were dried over sodium hydroxide, filtered,and concentrated to dryness, and the residue was taken up by hydrogenchloride in dioxane (4 M, 5 mL) and concentrated to dryness to give thetitle compound. ¹H NMR (500 MHz, CD₃OD): (free amine) δ 7.22-7.14 (m,4H), 7.06 (d, 2H), 6.96 (d, 2H), 3.22 (dd, 1H), 2.95 (dd, 1H), 2.86 (dd,1H), 1.16 (s, 3H), 1.10 (s, 3H).

REFERENCE EXAMPLE 26

2-Amino-5-methyl-3-phenylhexane hydrochloride salt

Step A 4-Methyl-2-phenylpentanoic acid

A solution of 0.25 g (1.84 mmol) of phenylacetic acid in 3.6 mL dry THFwas cooled in ice bath and 4 mL 1M lithium bis(trimethylsilyl)amide wasadded. After 15 min, 0.23 mL (2.02 mmol) of isobutyliodide was added andthe cold bath was removed. After stirring the reaction overnight, it wasquenched with water and extracted once with EtOAc. The aqueous layer wasacidified with 1.2 N HCl and extracted with EtOAc. The EtOAc solutionwas washed with brine, dried and concentrated to furnish the titlecompound which was used in the next step without purification. ¹H NMR:(500 MHz, CDCl₃): δ 0.92 (d, 6H), 1.51 (m, 1H), 1.72 (m, 1H), 1.98 (m,1H), 3.67 (m, 1H), 7.0-7.4 (m, 5H).

Step B N-Methoxy-N-methyl-4-methyl-2-phenylpentanamide

To a solution of 0.234 g (1.22 mmol) of 4-methyl-2-phenylpentanoic acidin 6 mL CH₂Cl₂ and 2 drops of DMF, 0.12 mL (1.34 mmol) of oxalylchloride was added. The solution was stirred for 1 h and concentrated.The residue was dissolved in 1 mL CH₂Cl₂ and added to a mixture of 0.142g N,O-dimethylhydroxylamine hydrochloride in 4 mL CH₂Cl₂and 4 mLsaturated NaHCO₃. After stirring for 4 h, the layers were separated andthe aqueous layer was extracted with CH₂Cl₂. The combined CH₂Cl₂ layerwas washed with brine, dried and concentrated to give the title compoundwhich was used in the next step without purification. ¹H NMR: (500 MHz,CDCl₃): δ 0.94 and 0.96 (2d, 6H), 1.5 (m, 1H), 1.67 (m, 1H), 2.0 (m,1H), 3.19 (s, 3H), 3.54 (s, 3H), 4.18 (br, 1H), 7.2-7.4 (m, 5H).

Step C 5-Methyl-3-phenyl-2-hexanone

To a solution of 75 mg (0.317 mmol)N-methoxy-N-methyl-4-methyl-2-phenylpentanamide in 1 mL dry THF, 0.45 mL1.4 M methylmagnesium bromide was added. The reaction was stirred for 1h, quenched with 1.2 N HCl and extracted with EtOAc. The EtOAc solutionwas washed with brine, dried and concentrated leaving the titlecompound. ¹H NMR: (500 MHz, CDCl₃): δ 0.95 (2d, 6H), 1.42 (m, 1H), 1.67(m, 1H), 1.9 (m, 1H), 2.06 (s, 3H), 3.73 (m, 1H), 7.0-7.4 (m, 5H).

Step D 5-Methyl-3-phenyl-2-hexanol

A solution of 66 mg (0.345 mmol) of 5-methyl-3-phenyl-2-hexanone in 1 mLMeOH was treated with 16 mg sodium borohydride. After 1.5 h, thereaction was quenched with 1.2 N HCl and concentrated. The residue waspartitioned between EtOAc and water. The organic layer was washed withbrine, dried and concentrated to yield the crude title compound whichwas used without purification. ¹H NMR: (500 MHz, CDCl₃): δ 0.88 (2d,6H), 1.0-1.8 (m, 4H), 1.2 (d, 3H), 2.64 (m, 1H), 3.9 (m, 1H), 7.2-7.4(m, 5H).

Step E 2-Azido-5-methyl-3-phenylhexane

To a solution of 60 mg 5-methyl-3-phenyl-2-hexanol in 2 mL CH₂Cl₂, 0.163g (0.62 mmol) of triphenylphosphine and 96 mg (0.31 mmol) of zinc azidepyridine were added. The reaction mixture was cooled in an ice bath and98 mL (0.62 mmol) of DEAD was added. The cold bath was removed and thesolution was stirred for 3 h. The reaction mixture was filtered througha pad of CELITE diatomaceous earth and the pad was rinsed with CH₂Cl₂.The filtrate was concentrated and the residue was purified by prep-TLCusing 20% EtOAc-hexane to isolate the title compound. ¹H NMR: (500 MHz,CDCl₃): δ 0.88 (2d, 6H), 1.12 (d, 3H), 1.31 (m, 1H), 1.72 (m, 2H), 2.68(m, 1H), 3.53 (m, 1H), 7.2-7.4 (m, 5H).

Step F 2-Amino-5-methyl-3-phenylhexane.

To a solution of 32 mg 2-azido-5-methyl-3-phenylhexane in 1 mL MeOH and2 drops of 1.2 N HCl, 4 mg PtO₂ was added and the solution was stirredunder H2 atmosphere for 2 h. The reaction was filtered through a pad ofCELITE diatomaceous earth and the pad was rinsed with MeOH. The combinedfiltrate was concentrated to give the desired product. ¹H NMR: (500 MHz,CDCl₃): δ0.86 (m, 6H), 0.99 (d, 3H), 1.25 (m, 1H), 1.54 (m, 1H), 1.77(m, 1H), 2.73 (m, 1H), 3.19 (m, 1H), 7.2-7.4 (m, 5H).

REFERENCE EXAMPLE 27

2-(2-Fluorophenyloxy)-2-methylpropionic acid

Step A 2-(2-Fluorophenyloxy)-2-methylpropionic acid

To a solution of 2-fluorophenol (2.0 g, 18 mmol) and1,1,1-trichloro-2-methyl-2-propanol (7.9 g, 45 mmol) in acetone (100 mL)was added sodium hydroxide (7.1 g, 0.18 mol), and an ice-water bath wasperiodically applied to maintain a gentle reflux. After the refluxsubsided, the reaction was stirred for one additional hour. The volatilematerials were removed on a rotary evaporator, and the residuepartitioned between ether (100 mL), hexane (100 mL) and water (200 mL).The aqueous layer was separated and acidified with concentratedhydrochloric acid (pH=2), and extracted with ether (3×100 mL). Thecombined extracts were dried over anhydrous MgSO₄, filtered, andconcentrated to dryness to give the title compound, which was usedwithout further purification. ¹H NMR (500 MHz, CD₃OD): δ 7.15-7.05 (m,4H), 1.56 (s, 6H). LC-MS: m/e 199 (M+1)⁺ (2.3 min).

The acids of Reference Examples 28-38 were prepared following theprocedures described for Reference Example 27 substituting2-fluorophenol with appropriately substituted phenols.

REFERENCE EXAMPLE 28

2-(3-Fluorphenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 7.26 (ddd, 1H), 6.77-6.70 (m, 2H), 6.64 (dt,1H), 1.59 (s, 6H). LC-MS: m/e 199 (M+1)⁺, (2.4 min).

REFERENCE EXAMPLE 29

2-(4-Fluorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 7.02-6.92 (m, 4H), 1.54 (s, 6H).

REFERENCE EXAMPLE 30

2-(3-Chlorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 7.23 (t, 1H), 7.00 (dd, 1H), 6.93 (t, 1H),6.84 (dd, 1H), 1.59 (s, 6H). LC-MS: m/e 215 (M+1)⁺, (2.7 min).

REFERENCE EXAMPLE 31

2-(3-Cyanophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 7.44 (dd, 1H), 7.36 (d, 1H), 7.22 (m, 2H),1.62 (s, 6H).

REFERENCE EXAMPLE 32

2-(3,4-Difluorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 7.16 (q, 1H), 6.86 (dddd, 1H), 6.72 (m, 1H),1.57 (s, 6H). LC-MS: m/e 217 (M+1)⁺, (2.5 min).

REFERENCE EXAMPLE 33

2-(3,5-Difluorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 6.56 (m, 1H), 6.47 (m, 2H), 1.60 (s, 6H).

REFERENCE EXAMPLE 34

2-(3,4-Dichlorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 7.40 (dd, 1H), 7.07 (d, 1H), 6.85 (dd, 1H),1.60 (s, 6H).

REFERENCE EXAMPLE 35

2-(3,5-Dichlorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 7.05 (t, 1H), 6.84 (d, 2H), 1.60 (s, 6H).

REFERENCE EXAMPLE 36

2-(3-Chloro-4-fluorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 7.16 (t, 1H), 7.05 (dd, 1H), 6.90 (td, 1H),1.57 (s, 6H).

REFERENCE EXAMPLE 37

2-(4-Chloro-3-fluorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 7.36 (t, 1H), 6.80 (dd, 1H), 6.74 (dd, 1H),1.60 (s, 6H).

REFERENCE EXAMPLE 38

2-(3,4,5-Trifluorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 6.68 (dd, 2H), 1.60 (s, 6H).

REFERENCE EXAMPLE 39

2-(2-Pyridyloxy)-2-methylbutanoic acid

Step A Benzyl 2-(2-Pyridyloxy)propionate

To a mixture of 2-hydroxypyridine (2.9 g, 30 mmol), benzyl lactate (5.0g, 21 mmol) and triphenylphosphine (12 g, 47 mmol) in 100 mL CH₂Cl₂ wasadded diethylazodicarboxylate (7.8 mL, 45 mmol) at 0° C. The reactionwas allowed to warm to room temperature for 4 h. The resulting mixturewas diluted with hexane (100 mL) and concentrated with 20 g silica gel.The material was loaded onto a silica gel column, which was eluted with10% EtOAc in hexane to give the title compound.

¹H NMR (500 MHz, CD₃OD): δ 8.00 (dd, 1H), 7.68 (ddd, 6H), 7.36-7.28 (m,5 H), 6.94 (dd, 1H), 6.84 (dd, 1H), 5.30 (q, 1H), 5. 18 (s, 2H), 1.59(d, 3H). LC-MS: m/e 258 (M+H)⁺ (3.3 min).

Step B Benzyl 2-(2-Pyridyloxy)-2-methylbutanoate.

To a solution of benzyl 2-(2-pyridyloxy)propionate (1.6 g, 6.2 mmol) andethyl iodide (1.5 mL, 25 mmol) in 10 mLanhydrous THF at −78° C. wasadded sodium hexamethyldisilazide (1 M in THF, 9.3 mL, 9.3 mmol)(potassium hexamethyldisilazide in toluene may be used with similarresults). The reaction was allowed to warm to room temperature over 2 hand was partitioned between saturated ammonium chloride (100 mL) andEtOAc (100 mL). The organic layer was separated and the aqueous layerextracted with EtOAc (2×50 mL). The combined organic extracts were driedover anhydrous sodium sulfate, filtered, and concentrated to dryness,and the residue was purified by flash column chromatography on silicagel eluted with 10% ETOAc in hexane to give the title compound. ¹H NMR(500 MHz, CD₃OD): δ 7.87 (dd, 1H), 7.63 (ddd, 1H), 7.27 (m, 3H), 7.18.(m, 2H), 6.85 (dd, 1H), 6.74 (dd, 1H), 5.08 (ABq, 2H), 2.13 (m, 1H),1.94 (m, 1H), 1.65 (s, 3H), 0.95 (t, 3H). LC-MS: m/e 286 (M+H)⁺ (3.8min).

Step C 2-(2-Pyridyloxy)-2-methylbutanoic Acid

A mixture of benzyl 2-(2-pyridyloxy)-2-methylbutanoate (1.6 g, 5.5 mmol)and 10% palladium on carbon (50 mg) in 50 mL MeOH was degassed andfilled with hydrogen using a balloon. After stirring at room temperatureovernight, the reaction mixture was filtered through CELITE diatomaceousearth and washed with MeOH (20 mL), and the filtrate was concentrated todryness to give the title compound. ¹H NMR (500 MHz, CD₃OD): δ 8.03 (dd,1H), 7.64 (ddd, 1H), 6.89 (dd, 1H), 6.76 (dd, 1H), 2.14 (m, 1H), 1.94(m, 1H), 1.64 (s, 3H), 0.99 (t, 3H). LC-MS: m/e 196 (M+H)⁺ (1.8 min).

REFERENCE EXAMPLE 40

2-(2-Pyridyloxy)-2-methylpropionic Acid

The title compound was prepared following the procedures described forReference Example 39 substituting ethyl iodide and sodiumhexamethyldisilazide with methyl iodide and potassiumhexamethyldisilazide respectively at Step B.

¹H NMR (500 MHz, CD₃OD): δ 8.04 (dd, 1H), 7.64 (ddd, 1H), 6.89 (dd 1H),6.76 (dd, 1H), 1.66 (s, 6H). LC-MS: m/e 182 (M+H)⁺ (1.5 min).

REFERENCE EXAMPLE 41

2-(3-Pyridyloxy)-2-methylpropionic Acid

The title compound was prepared following the procedures described forReference Example 39 substituting 2-hydroxypyridine with3-hydroxypyridine at Step A and ethyl iodide with methyl iodide at StepB. ¹H NMR (500 MHz, CD₃OD): δ 8.21 (d, 1H), 8.19 (dd, 1H), 7.43-7.35 (m,2H), 1.62 (s, 6H). LC-MS: m/e 182 (M+H)⁺ (0.3 min).

REFERENCE EXAMPLE 42

2-(4-Pyridyloxy)-2-methylpropionic Acid

Step A N-Trimethylsilylethoxymethyl-4-pyridone.

To a solution of 4-hydroxypyridine (3.0 g, 32 mmol) andtrimethylsilylethoxymethyl chloride (5.5 mL, 32 mmol) in 30 mLacetonitrile was added cesium carbonate (11 g, 34 mmol). After stirringat room temperature overnight, the reaction mixture was partitionedbetween brine (100 mL) and EtOAc (100 mL). The organic layer wasseparated and aqueous layer extracted with EtOAc (3×100 mL). Thecombined extracts were dried over anhydrous sodium sulfate, filtered,and concentrated to dryness to give the title compound contaminated withsome O-alkylated product. ¹H NMR (500 MHz, CD₃OD): δ 7.92 (d, 2H), 6.49(d, 2H), 5.28 (s, 2H), 3.62 (t, 2H), 0.96 (t, 2H), 0.024 (s, 9H).

Step B Benzyl 2-(4-Pyridyloxy)propionate

To a solution of benzyl lactate (6.0 g, 33 mmol) and N-methyl morpholine(2.7 mL, 33 mmol) in 100 mL anhydrous CH₂Cl₂ at −20° C. was addedtrifluoromethanesulfonyl anhydride (5.6 mL, 33 mmol). After stirring at−20° C. for 1 h, the reaction mixture was diluted with 100 mL hexane andwashed with dilue aqueous sodium hydrogen sulfate and brine/saturatedaqueous sodium bicarbonate. The organic layer was separated, dried overanhydrous MgSO₄, filtered, and concentrated to dryness, and the residuewas purified by flash column chromatography on silica gel eluted with10% ether in hexane to give benzyl2-trifluoromethanesulfonyloxypropionate (6.4 g), which was usedimmediately for the ensuing reaction. Thus, a mixture ofN-trimethylsilylethoxymethyl-4-pyridone (Step A, 3.4 g, 15 mmol) andbenzyl 2-trifluromethanesulfonyloxypropionate (4.7 g, 15 mmol) washeated at 60° C. overnight. After cooling to room temperature, thereaction mixture was dissolved in CH₂Cl₂ and loaded onto a silica gelcolumn, which was eluted with 5% MeOH in CH₂Cl₂ to give the titlecompound. ¹H NMR (500 MHz, CD₃OD): δ 8.57 (d, 2H), 7.42 (d, 2H), 7.4-7.3(m, 5H), 5.44 (q, 1H), 5.24 (ABq, 2H), 1.72 (d, 3H). LC-MS: m/e 258(M+H)⁺ (1.8 min).

Step C 2-(4-Pyridyloxy)-2-methylpropionic acid

The product of Step B (4.5 g, 18 mmol) was converted to the titlecompound following the procedure described on Reference Example 39,Steps B-C substituting benzyl 2-(2-pyridyloxy)propionate and ethyliodide with benzyl 2-(4-pyridyloxy)propionate and methyl iodide at StepB. ¹H NMR (500 MHz, CD₃OD): δ 8.44 (d, 2H), 7.14 (d, 2H), 1.70 (s, 6H).LC-MS: m/e 18 (M+H)⁺ (0.28 min).

REFERENCE EXAMPLE 43

2-(2-Methoxyphenyloxy)propenoic Acid

Step A Methyl 2-(2-Methoxyphenyloxy)propenoate.

To a solution of 2,3-dihydro-1,4-benzodioxine-2-carboxylic acid (1.0 g,5.6 mmol) in CH₂Cl₂ (10 mL) and MeOH (10 mL) at 0° C. was addedtrimethylsilyldiazomethane (2 M in hexane) until yellow color persisted,and the reaction was stirred at room temperature for 15 min. Thereaction mixture was concentrated to dryness and azeotroped withtoluene. The residue was dissolved in anhydrous THF (20 mL), and wasadded methyl iodide (1.8 mL, 28 mmol) and potassium hexamethyldisilazide(0.5 M in toluene, 17 mL, 8.5 mmol) at −78° C. The reaction was allowedto warm to room temperature over 4 h, diluted with EtOAc (100 mL),washed with saturated ammonium chloride (100 mL) and water (100 mL),dried over anhydrous sodium sulfate, filtered, and concentrated todryness to give the title compound. ¹H NMR (500 MHz, CD₃OD): δ 7.07(ddd, 1H), 6.97 (dd, 1H), 6.94 (dd, 1H), 6.85 (ddd, 1H), 5.52 (d, 1H),4.64 (d, 1H), 3.86 (s, 3H), 3.83 (s, 3H). LC-MS: m/e 231 (M+Na)⁺ (2.6min).

Step B 2-(2-Methoxyphenyloxy)propenoic Acid.

To a solution of methyl 2-(2-methoxyphenyloxy)propenoate (0.30 g, 1.4mmol) in THF (30 mL) and water (30 mL) was added lithium hydroxidemonohydrate 0.17 g, 4.0 mmol). After stirring at room temperatureovernight, the reaction was quenched by addition of concentratedhydrochloric acid (final pH=2), and the product was extracted with EtOAc(3×100 mL). The combined extracts were dried over anhydrous sodiumsulfate, filtered, and concentrated to dryness to give the titlecompound. ¹H NMR (500 MHz, CD₃OD): δ 7.42 (ddd, 1H), 7.22 (dd, 1H), 7.10(dd, 1H), 6.97 (ddd, 1H), 5.48 (d, 1H), 4.51 (d, 1H), 3.64 (s, 3H).

REFERENCE EXAMPLE 44

2,2-Dimethyl-3-phenylpropionic acid

Step A 1-Phenyl-2-chloro-2-methylpropane.

A mixture of 5.92 g (40 mmoles) of 1-phenyl-2-hydroxy-2-methylpropaneand 50 mL conc. hydrochloric acid was stirred at ice bath temperaturefor 1 h and at RT for 3 h. The reaction mixture was then extracted withether. The organic layer was dried over MgSO₄. Solvent removal gave1-phenyl-2-chloro-2-methylpropane.

Step B 2,2-Dimethyl-3-phenylpropionic acid.

A mixture of 3.36 g (20 mmol) of the above chloride, and 560 mg (23mmol) of magnesium turnings in 20 mL THF containing 0.01 mL1,2-dibromoethane was stirred for 4 h at RT Most of the metal wasdigested. Carbon dioxide from dry ice in a flask connected with a hosewas bubbled for 3 h. The reaction mixture was then stirred overnight atRT and quenched with 1N HCl. This was then extracted with EtOAc. Theorganic phase was dried over MgSO₄. Solvent removal gave a residue,which was partitioned between ether and 2N NaOH. The aqueous layer waswashed with ether then acidified with 2N HCl and extracted with EtOAc.The EtOAc solution was dried over MgSO₄. The solvent was removed invacuo to give the desired 2,2-dimethyl-3-propionic acid as an oil. NMR:1.22 (s; 6H), 2.9 (s, 2H), 7.15-7.34 (m, 5H).

REFERENCE EXAMPLE 45

2-Methyl-3-(4-chlorophenyl)propionic acid

A solution of 3-(4-chlorophenyl)propionic acid (1.85 g, 10 mmol) in 10mL THF was added to 16 mL freshly prepared 1.5 M LDA (24 mmol) atdryice-acetone bath temp. The reaction mixture was stirred 1 hr as itwarmed to −30° C. and 1.6 mL (25 mmol) of methyl iodide was added. Theresulting mixture was stirred at the same temp. for 0.5 h and thestirring was continued at RT overnight. The reaction was quenched with 1N HCl, and diluted with ether. The solution was washed with water, 10%sodium thiosulfate and brine. The organic layer was dried over MgSO₄.Solvent removal gave a mixture of the desired methylated product and thestarting acid. Repetition of the above procedure on this residue gave1.3 g the desired 2-methyl-3-(4-chlorophenyl) propionic acidcontaminated with ˜5% of the starting acid as an oil. NMR: 1.5 (d, 3H),4.78 (q, 1H). 6.84 & 7.26 (2d, 4H).

REFERENCE EXAMPLE 46

N-[3-(4-Chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]aminehydrochloride (Diastereomer α)

The title compounds was prepared following the procedures described forReference Example 10 substituting methyl phenylacetate with methyl3,5-difluorophenylacetate (prepared from 3,5-difluorophenylacetic acidand trimethylsilyldiazomethane) at Step A and sodium borohydride in MeOHwith lithium tri(sec-butylborohydride in THF at Step E. LC-MS: m/e 296(M+H)⁺ (2.39 min).

REFERENCE EXAMPLE 47

N-[2-(3-Bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

The title compounds was prepared following the procedures described forReference Example 10 substituting methyl phenylacetate with methyl3-bromophenylacetate (prepared from 3-bromophenylacetic acid andtrimethylsilyldiazomethane) at Step A and sodium borohydride in MeOHwith lithium tri(sec-butylborohydride in THF at Step E. LC-MS: m/e 338(M+H)⁺ (2.5 min).

REFERENCE EXAMPLE 48

N-[3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]aminehydrochloride (Diastereomer α)

Step A2-(N-tert-Butoxycarbonyl)amino-4-(4-chlorophenyl)-3-(3-cyanophenyl)butane

To a solution of2-(N-tert-butoxycarbonyl)amino-3-bromophenyl-4-(4-chlorophenyl)butane(Intermediate of Reference Example 47 1.0 g, 2.3 mmol) in 5 mL DMF wasadded zinc cyanide (0.16 g, 1.4 mmol),tris(dibenzylidene-acetone)dipalladium chloroform complex (3.0 mg, 2.8μmol), 1,1′-bis(diphenylphosphino)ferrocene (5.0 mg, 9.0 μmol) and water(0.1 mL). After heating at 120° C. for 6 h under nitrogen, another batchof zinc cyanide (0.16 g, 1.4 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (5.0 mg, 4.8μmol), 1,1′-bis(diphenylphosphino)ferrocene (5.0 mg, 9.0 μmol) and water(0.05 mL) was added, and heating was continued for another 18 h. Aftercooling to room temperature, the resulting mixture was partitionedbetween water (50 mL) and ether (50 mL). The organic layer was separatedand the aqueous layer extracted with ether (2×50 mL). The combinedextracts were dried over anhydrous Mg₂SO₄, filtered and concentrated,and the residue was purified by flash column chromatography on silicagel eluted with 20% EtOAc in hexane to afford the title compound. ¹H NMR(400 MHz, CD₃OD): δ 7.6-7.3 (m, 4H), 7.10 (d, 2H), 6.92 (d, 2H), 3.88(m, 1H), 3.20 (m, 1H), 2.97 (m, 1H), 1.82 (m, 1H), 1.45 (s, 9H), 0.94(d, 3H). LC-MS: m/e 385 (M+H)⁺ (3.9 min).

Step B N-[3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]aminehydrochloride (Diastereomer α)

The title compound was prepared following the procedure described forReference Example 10, Step I. LC-MS: m/e 285 (M+H)⁺ (2.2 min).

REFERENCE EXAMPLE 49

N-[2-(3-Chlorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]aminehydrochloride (Diastereomer α)

Step A2-(N-tert-Butoxycarbonyl)amino-4-(4-chlorophenyl)-3-(3-trimethylstannylphenyl)butane

To a solution of2-(N-tert-butoxycarbonyl)amino-3-(3-bromophenyl)-4-(4-chlorophenyl)butane(intermediate of Reference Example 47, 1.5 g, 3.4 mmol) in 15 mLanhydrous dioxane was added hexamethylditin (1.6 g, 4.8 mmol),triphenylphosphine (18 mg, 0.068 mmol), lithium chloride (0.16 g, 3.8mmol) and tetrakis(triphenyl-phosphine)palladium (0.20 g, 0.17 mmol).After heating at 95° C. for 7.5 h under nitrogen, the reaction mixturewas cooled to room temperature, diluted with EtOAc (100 mL), washed with10% aqueous potassium fluoride and brine, dried over anhydrous Mg₂SO₄,filtered and concentrated to dryness. The residue was purified by flashcolumn chromatography on silica gel eluted with 20% EtOAc in hexane toafford the title compound. ¹H NMR (500 MHz, CD₃OD): δ 7.3-7.2 (m, 2H),7.07 (d, J=8.5 Hz, 2H), 7.06-6.99 (m, 2H), 6.86 (d, J=8.5 Hz, 2H), 3.93(m, 1H), 3.18 (m, 1H), 2.76 (m, 2H), 1.51 (s, 9H), 0.94 (d, J=7.0 Hz,3H), 0.21 (s, 9H).

Step B2-(N-tert-Butoxycarbonyl)amino-3-(3-chlorophenyl)-4-(4-chlorophenyl)butane

To a solution of2-(N-tert-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-(3-trimethylstanylphenyl)butane(0.55 g, 1.0 mmol) in 5 mL CH₂Cl₂ at 0° C. was added tert-butoxychloride(freshly prepared, 0.20 mL, 1.1 mmol). The reaction was allowed to warmto room temperature over 2 h, and the resulting mixture was concentratedwith 2 g silica gel. The residue was purified by flash columnchromatography on silica gel eluted with 10% ether in hexane to affordthe title compound. ¹H NMR (500 MHz, CD₃OD): δ 7.25-7.15 (m, 2H), 7.11(d, J=8.5 Hz, 2H), 7.09 (m, 1H), 6.99 (d, J=7.5 Hz, 1H), 6.92 (d, J=8.5Hz, 2H), 3.88 (m, 1H), 3.19 (dd, J=13.0, 3.5 Hz, 1H), 2.90-2.75 (m, 2H),1.50 (s, 9H), 0.94 (d; J=6.5 Hz).

Step C N-[2-(3-Chloroophenyl)-3-(4-chlorophenyl)-1-methylpropyl]aminehydrochloride (Diastereomer α)

The title compound was prepared following the procedure described forReference Example 10, Step I. LC-MS: m/e 294 (M+H)⁺ (2.82 min).

REFERENCE EXAMPLE 50

N-[2-(3-Bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl]aminehydrochloride andN-[3-(4-Chlorophenyl)-2-(3-iodophenyl)-1-methylpropyl]aminehydrochloride (1:1 Mixture) (Diastereomer α)

Step A2-(N-tert-Butoxycarbonyl)amino-3-(3-bromophenyl)-4-(4-chlorophenyl)-butaneand2-(N-tert-Butoxycarbonyl)amino-4-(4-chlorophenyl)-3-(3-iodophenyl)butane

To a solution of2-(N-tert-butoxycarbonyl)amino-3-(3-bromophenyl)-4-(4-chlorophenyl)butane(intermediate of Reference Example 47, 2.6 g, 5.9 mmol) in 7 mLanhydrous THF at 0° C. was added methylmagnesium chloride (3 M in THF,3.9 mL, 12 mmol). After 30 min, the reaction mixture was cooled to −78°C., and was added tert-butyllithium (1.7 M, 10 mL, 17 mmol). Afterstirring at −78° C. for 2 h, the reaction was allowed to warm to 0° C.,and half of the resulting mixture was added to a suspension of iodine(5.0 g, mmol) in 10 mL THF at −40° C. The reaction mixture was allowedto warm to room temperature over 2 h, and was partitioned between ether(100 mL) and saturated aqueous ammonium chloride (100 mL). The organiclayer was separated and the aqueous layer extracted with ether (2×50mL). The combined extracts were washed with dilute aqueous sodiumthiosulfate (2×) and brine, dried over anhydrous MgSO₄, filtered andconcentrated to dryness. The residue was purified by flash columnchromatography on silica gel eluted with 10% EtOAc in hexane to affordthe title compounds as a 1:1 mixture.

Step B N-[2-(3-Bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl]aminehydrochloride andN-[3-(4-chlorophenyl)-2-(3-iodophenyl)-1-methylpropyl]aminehydrochloride (1:1 Mixture) (Diastereomer α)

The title compound was prepared following procedure described forReference Example 10, Step I. LC-MS: m/e 338/386/(M+H)⁺ (2.6 min).

REFERENCE EXAMPLE 51

2-Methyl-2-(4-trifluoromethylphenyloxy)propionic acid

The title compound was prepared following the same procedure describedfor Reference Example 27. ¹H NMR (500 MHz, CD₃OD): δ 7.56 (d, 2H), 7.00(d, 2H), 1.62 (s, 6H).

REFERENCE EXAMPLE 52

2-Methyl-2-(3-chloro-5-fluorophenyloxy)propionic acid

Step A 3-Chloro-5-fluorophenol

To a solution of 1-bromo-3-chloro-5-fluorobenzene (16 g, 76 mmol) in 250mL anhydrous ether at −78° C. was added tert-butyllithium (1.7 M, 100mL, 170 mmol). After stirring at −78° C. for 1 h, trimethyl borate (20mL, 176 mmol) was added, and the reaction was allowed to warm to roomtemperature overnight. The resulting mixture was cooled to −10° C., andwas added peracetic acid (32% in acetic acid, 35 mL). After stirring at0° C. for 30 min, potassium bisulfite (5 g) was added. After stirring atroom temperature for 30 min, the aqueous layer was separated and theorganic mixture was extracted with 3 M aqueous sodium hydroxide (3×100mL). The aqueous extracts were acidified with concentrated hydrochloricacid (pH=2), and was extracted with ether (3×150 mL). The combined etherextracts were dried over anhydrous Mg₂SO₄, filtered and concentrated toafford the crude phenol, which was azeotroped with heptane (100 mL) toremove traces of acetic acid to give the title compound. ¹H NMR (500MHz, CD₃OD): δ 7.51 (br s, 1H), 7.35 (br d, 1H), 7.21 (m, 1H).

Step B 2-Methyl-2-(3-chloro-5-fluorophenyloxy)propionic acid

The title compound was prepared following the procedures described forReference Example 27. ¹H NMR (500 MHz, CD₃OD): δ 7.53 (br s, 1H), 7.36(br d, 1H), 7.20 (m, 1H), 1.24 (s, 6H).

REFERENCE EXAMPLE 53

2-Methyl-2-(3-pyridazinyloxy)propionic acid

The title compound was prepared following the procedures described forReference Example 39 substituting 2-hydroxpyridine with3-hydroxypyridazine at Step A and ethyl iodide with methyl iodide atStep B. ¹H NMR (500 MHz, CD₃OD): δ 7.98 (dd, 1H), 7.45 (dd, 1H), 6.96(dd, 1H), 1.70 (s, 6H).

REFERENCE EXAMPLE 54

2-Methyl-2-(5-chloro-2-pyridyloxy)propionic acid

Step A Ethyl 2-Methyl-2-(5-chloro-2-pyridyloxy)propionate

A mixture of 5-chloro-2-hydroxypyridine (5.0 g, 39 mmol), ethyl2-bromoisobutyrate (5.7 mL, 39 mmol) and cesium carbonate (25 g, 77mmol) in 50 mL acetonitrile was heated at 50° C. overnight. The volatilematerials were removed by concentrating on a rotary evaporator, and theresidue was partitioned between water (100 mL) and EtOAc (100 mL). Theorganic layer was separated and the aqueous layer extracted with EtOAc(2×100 mL). The combined organic extracts were dried over anhydroussodium sulfate, filtered and concentrated to dryness, and the residuewas purified by flash column chromatography on silica gel eluted with 5%EtOAc in hexane to give the title compound. ¹H NMR (500 MHz, CD₃OD): δ7.99 (d, 1H), 7.67 (dd, 1H), 6.68 (d, 1H), 4.13 (q, 2H), 1.64 (s, 6H),1.14 (t, 3H). LC-MS: m/e 244 (M+H)⁺ (3.41 min).

Step B 2-Methyl-2-(5-chloro-2-pyridyloxy)propionic Acid

A mixture of ethyl 2-methyl-2-(5-chloro-2-pyridyloxy)propionate andsodium hydroxide (0.85 g, 21 mmol) in 15 mL acetonitrile and 15 mL waterwas heated at 50° C. overnight. The volatile materials were removed byconcentrating on a rotary evaporator, and the residue was partitionedbetween 2 M hydrochloric acid (100 mL) and ether (100 mL). The organiclayer was separated and washed with water (2×50 mL), dried overanhydrous MgSO₄, filtered and concentrated to dryness to give the titlecompound. ¹H NMR (500 MHz, CD₃OD): δ 8.02 (d, 1H), 7.65 (dd, 1H), 6.77(d, 1H), 1.62 (s, 6H). LC-MS: m/e 216 (M+H)⁺ (2.33 min).

REFERENCE EXAMPLE 55

2-Methyl-2-(5-trifluoromethyl-2-pyridyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 54 substituting 5-chloro-2-hydroxpyridine with5-trifluoromethyl-2-hydroxpyridine at Step A. ¹H NMR (500 MHz, CD₃OD): δ8.38 (br s, 1H), 7.93 (dd, 1H), 7.13 (d, 1H), 1.70 (s, 6H). LC-MS: m/e250 (M+H)⁺ (2.6 min).

REFERENCE EXAMPLE 56

2-Methyl-2-(6-methyl-2-pyridyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 54 substituting 5-chloro-2-hydroxpyridine with6-methyl-2-hydroxpyridine at Step A. ¹H NMR (500 MHz, CD₃OD): δ 7.51 (t,1H), 6.74 (d, 1H), 6.53 (d, 1H), 2.34 (s, 3H), 1.64 (s, 6H). LC-MS: m/e196 (M+H)⁺ (1.3 min).

REFERENCE EXAMPLE 57

2-Methyl-2-(4,6-dimethyl-2-pyridyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 54 substituting 5-chloro-2-hydroxpyridine with4,6-dimethyl-2-hydroxpyridine at Step A. LC-MS: m/e 210 (M+H)⁺ (1.17min).

REFERENCE EXAMPLE 58

2-Amino-4-(4-chlorophenyl)-3-cyclobutylmethoxybutane

Step A Methyl 2-diazo-3-(4-chlorophenyl)propanoate.

DL-4-Chlorophenylalanine methyl ester (5.0 g, 23.36 mmol) was dissolvedin 120 mL chloroform and placed into an oven-dried 3-neck flask equippedwith a condenser and an addition funnel. Glacial acetic acid (0.267 mL,4.672 mmol) was added. Finally, isoamylnitrite (3.8 mL, 28 mmol) wasadded dropwise while slowly bringing the reaction to reflux (73° C.).The reaction was refluxed for 30 minutes and then cooled to 0° C. Thereaction mixture was washed with cold 1 N sulfuric acid solution, coldwater, cold saturated aqueous sodium bicarbonate solution, and then coldwater again. The organic extracts were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude mixture was purified byflash chromatography (Biotage 40M cartridge, gradient elution usinghexane and EtOAc (100:1 to 50:1) to provide a yellow oil, homogeneous byTLC, R_(f)=0.48 (4:1 hexanes:EtOAc). 500 MHz ¹H NMR (CDCl₃): δ 3.65 (s,2H); 3.83 (s, 3H); 7.22 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5, 2H).

Step B Methyl 3-(4-chlorophenyl)-2-cyclobutylmethoxypropanoate.

To a solution of 500 mg (2.23 mmol) ofmethyl-2-diazo-3-(4-chlorophenyl)propanoate (obtained from Step A) and1.05 mL (5 eq; 11.1 mmol) of cyclobutanemethanol in 5 mL benzene in apressure tube was added 10 mg (1 mole %) of Rh₂(OAc)₄ catalyst. The tubewas sealed and heated to 90° C. for 1.5 h. The solvents were evaporatedunder reduced pressure and the crude material was taken up in CH₂Cl₂ andpurified by flash chromatography via gradient elution using mixtures ofhexane and EtOAc (100:1 to 50:1). This provided the title compound as aclear oil. TLC R_(f)=0.53 (4:1 hexanes:EtOAc). 500 MHz ¹H NMR (CDCl₃): δ1.68 (m, 2H); 1.85 (m, 1H); 1.88 (m, 1H); 2.01 (m, 2H); 2.53 (sep, 1H);2.98 (m, 2H); 3.24 (dd, 1H); 3.58 (dd, 1H); 3.76 (s, 3H); 3.98 (dd, 1H);7.20 (d, 2H); 7.28 (d, 2H).

Step C 4-(4-Chlorophenyl)-3-cyclobutylmethoxybutan-2-one.

At 0° C., under anhydrous conditions, to a stirred suspension ofN,O-dimethylhydroxylaminehydrochloride (732 mg, 7.50 mmol) in 60 mLCH₂Cl₂ was added dimethylaluminum chloride (7.5 mL, 1M solution inhexanes). The solution was allowed to warm to room temperature over aperiod of one hour. At that point a solution of methyl2-cyclobutylmethoxy-3-(4-chlorophenyl)propanoate (531 mg, 1.88 mmol,obtained from Step B) in CH₂Cl₂ (8 mL) was added dropwise. The reactionwas allowed to stir overnight at room temperature when TLC indicatedcompletion of reaction. The reaction was worked up by the addition ofpH=8 phospate buffer (25 mL, approx. 3 mL/mmol of Me₂AlCl) and allowedto stir at room temperature for 30 minutes, diluted with chloroform (75mL), and the phases were separated. The organic layer was washed withwater and dried over MgSO₄. The solvents were evaporated under reducedpressure and the crude product was purified by flash chromatography(gradient elution using hexane and EtOAc, 20:1 to 5:1) to give theWeinreb amide as a clear oil). This purified material (424 mg, 1.36mmol) was dissolved in 10 mL THF, injected into an oven dried flask, andcooled to 0° C. under nitrogen. Methyl magnesium bromide (1.4 mL 3Msolution in ether) was added to the solution dropwise. The reaction wasallowed to warm to room temperature. After 4 h the TLC indicated acomplete reaction. The reaction was quenched with enough 10% citric acidto bring the pH of the solution to approximately 3. The aqueous layerwas extract with ether. The combined organics were washed with water andthen dried over MgSO₄. The solvents were evaporated under reducedpressure and the crude material was purified by flash chromatography(hexane:EtOAc, 100:1 to 50:1), resulting in 250 mg the title compound asa clear oil. TLC R_(f)=0.55 (4:1 hexanes:EtOAc). 500 MHz ¹H NMR (CDCl₃):δ 1.71 (m, 2H); 1.84 (m, 1H); 1.91 (m, 1H); 2.01 (m, 2H); 2.17 (s, 3H);2.53 (sep, 1H); 2.90 (m, 2H); 3.28 (dd, 1H); 3.43 (dd, 1H); 3.81 (dd,1H).

Step D 2-Amino-4-(4-chlorophenyl)-3-cyclobutylmethoxybutane.

A solution of 3-cyclobutylmethoxy-4-(4-chlorophenyl)butan-2-one (247 mg,0.925 mmol, obtained from Step C) in 0.5 mL CH₂Cl₂ was added to astirred suspension of NH₄OAc (715 mg, 9.25 mmol) and NaBH₃CN (35 mg,0.555 mmol) at room temperature and allowed to stir overnight. Thereaction was quenched by the addition of 2.2 mL conc. HCl allowed tostir for 30 minutes. The solvents were evaporated under reduced pressureand the residue was partitioned between ether and water. The aqueouslayer was washed two more times with ether. The combined organics weredried over Na₂SO₄. The crude product mixture obtained after filtrationand removal of volatiles was purified by flash chromatography, elutingusing mixtures of mixtures of CH₂Cl₂ and MeOH (100% CH₂Cl₂, to 5% MeOHin CH₂Cl₂) to provide the title compound as a yellow oil, homogeneous byTLC R_(f)=0.12 (5% MeOH in CH₂Cl₂). 500 MHz ¹H NMR (CDCl₃): δ 1.16 (t,3H); 1.67 (m, 2H); 1.85 (m, 3H); 2.01 (m, 2H); 2.48 (m, 1H); 2.74 (m,2H); 2.90 (dd, 1H); 3.15 (d quint, 2H); 3.37 (m, 2H).

2-Amino-4-(4-chlorophenyl)-3-methoxy-butane,2-amino-4-(4-chlorophenyl)-3-ethoxy-butane,2-amino-4-(4-chlorophenyl)-3-n-propyloxy-butane,2-amino-4-(4-chlorophenyl)-3-n-pentyloxy-butane, and2-amino-4-(4-chlorophenyl)-3-cyclopentylmethoxy-butane were preparedaccording to the procedures described in Reference Example 58substituting an appropriate alcohol for cyclobutylmethanol in Step B.

REFERENCE EXAMPLE 59

2-Amino-4-(4-chlorophenyl)-3-(1-pyrrolidinyl)-butane hydrochloride

Step A Ethyl 3-(4-chlorophenyl)-2-pyrrolidin-N-yl-propanoate.

While stirring rapidly, to a mixture of DL-4-chlorophenylalanine methylester hydrochloride (2.5 g, 10 mmole), 40 mL ethanol and sodiumcarbonate (3.18 g, 30 mmole) was added dropwise a solution of1,4-dibromobutane (2.16 g, 10 mmol) dissolved in 20 mL ethanol. Themixture was refluxed overnight. The volatiles were removed under reducedpressure, and the residue was partitioned between water and EtOAc. Theaqueous layer was re-extracted with EtOAc thrice. The organic layerswere combined and washed tieh water and brine and dried over anhydrousMgSO₄. The crude product obtained after filtration and removal ofvolatiles was purified via flash chromatography using mixtures of CH₂Cl₂and MeOH to provide the titled compound as an oil, homogeneous by TLC,R_(f)=0.55 in 95:5 CH₂Cl₂:MeOH. LC/MS m/e=282.1 (M+1). 400 MHz ¹H NMR(CDCl₃) δ 1.12 (t, J=7.2 Hz, 3H), 1.72 (m, 4H), 2.67 (m, 1H), 2.76 (m,1H), 3.05 (m, 4H), 3.43 (m, 1H), 4.05 (m, 2H), 7.13 (d, J=8.2 Hz, 2H),7.24 (d, J=8.2 Hz, 2H)

Step B 4-(4-Chlorophenyl)-3-(1-pyrrolidinyl)-butan-2-one.

The title compound was prepared according to the procedure of ReferenceExample 10, Step C except that ethyl3-(4-chlorophenyl)-2-(1-pyrrolidinyl)-propanoate (from Step A) was theester used (two steps). TLC R_(f)=0.7 (95:5 CH₂Cl₂:MeOH). LC/MS m/e=252(M+1). 500 MHz ¹H NMR (CDCl₃) δ 1.86 (br s, 4H), 2.03 (s, 3H), 2.66 (m,2H), 2.78 (m, 2H), 2.98 (dd, J=2.9, 10.3 Hz, 1H), 3.08 (m, 1H), 3.43 (m,1H), 7.12 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H)

Step C 4-(4-Chlorophenyl)-3-pyrrolidin-N-yl-butan-2-one oxime

To a solution of 4-(4-chlorophenyl)-3-pyrrolidin-N-yl-butan-2-one (200mg, 0.79 mmol, from Step B) dissolved in ethanol (2 mL), was addedpyridine (63 mg, 0.79 mmol), and hydroxylamine hydrochloride (78 mg,1.12 mmol). The mixture was refluxed for 24 h when LC/MS indicateddisappearance of all starting material. The mixture was cooled to roomtemperature, concentrated under reduced pressure, treated with 33%aqueous potassium carbonated, and extracted with chloroform 5 times. Theorganic layers were combined and filtered over glass wool and dried overpotassium carbonate. The filtrated obtained after passing throughsintered glass was concentrated to give the oxime, homogeneous by TLC,R_(f)=0.3 in 95:5 CH₂Cl₂:MeOH. LC/MS m/e=267 (M+1). 500 MHz ¹H NMR(CDCl₃) δ 1.73 (m, 4H), 1.76 (s, 3H), 2.40 (m, 2H), 2.60 (m, 2H), 2.72(dd, J=2.7, 10.8 Hz, 1H), 2.94 (dd, J=4.3, 8.8 Hz, 1H), 3.03 (dd, J=4.4,13.3 Hz, 1H), 3.8 (s, 1H), 6.96 (d, J=8.3 Hz, 2H), 7.11 (d, J=8.3 Hz,2H)

Step D 2-Amino-4-(4-chlorophenyl)-3-pyrrolidin-N-yl-butanehydrochloride.

At room temperature, to a solution of4-(4-chlorophenyl)-3-pyrrolidin-N-yl-butan-2-one oxime (173 mg, 0.648mmol, from Step C) in 1.8 mL anhydrous THF was added dropwise a 1Msolution of lithium aluminum hydride in THF (0.778 mmole). The mixturewas refluxed for 20 h. The reaction was quenched by addition ofsaturated aqueous sodium sulfate (0.1 mL), and stirred overnight. Thismixture was filtered over a pad of CELITE diatomaceous earth, and thefiltrate was concentrated to dryness. The mass spectrum of this materiallooked very messy, so the HCl salt was prepared (by addition of a HCl(g)in ether solution) in attempt to clean up the mess. By NMR, thereductive amination provided a ˜1:1 mixture of the two diastereomericpairs of amines. This HCl salt was rather sticky and difficult to workwith and therefore was used in the ensuing coupling experiment withoutfurther purification.

LC/MS m/e=253 (M+1). 500 MHz ¹H NMR (CD₃OD) δ 1.56, 1.59 (2 d, J=7.2 Hz,3H), 2.03 (m, 6H), 2.08 (m, 2H), 3.20-4.00 (m, 3H), 7.43 (m, 4H)

REFERENCE EXAMPLE 60

Benzyl 3-amino-2-(4-chlorobenzyl)butyrate

Step A Benzyl 2-(4-chlorobenzyl)-3-ketobutyrate.

Benzyl acetoacetate (1.92 g, 10 mmole) and 4-chlorobenzylbromide (2.05g, 10 mmole) were dissolved in 40 mL anhydrous THF and cooled to −10° C.To this mixture was added dropwise slowly a solution of solution ofsodium hexamethyl disilazide (0.5M solution in THF). Monoalkylationoccurred almost exclusively of bisalkylation between −10 and 5° C. Afterquenching with water, the organics were extracted with EtOAc threetimes. The combined organic layer was washed with brine and dried overanhydrous MgSO₄. The crude product obtained after filtration and removalof volatiles was purified via flash chromatography using gradientelution (mixtures of hexane and EtOAc) to provide of the title compoundas a clear yellow liquid, homogeneous by TLC, R_(f)=0.4 in 4:1hexane:EtOAc. By NMR, this compound, this compound exists in a ˜4:1ratio of the keto:enol forms. 400 MHz ¹H NMR (CDCl₃) δ 2.08, 2.18 (2 s,3H), 3.15 (m, 2H), 3.80 (t, J=7.5 Hz, 0.8 H), 5.14, 5.17 (2 s, 2H),7.05-7.39 (m, 9H).

Step B Benzyl 3-amino-2-(4-chlorobenzyl)butyrate.

Benzyl 2-(4-chlorobenzyl)-3-ketobutyrate (317 mg, 1 mmole, obtained fromStep A) was added to a cooled mixture of 7M ammonia in MeOH (2.42 mL)and glacial acetic acid (1.6 mL). To this solution, at ˜10° C., wasadded sodium cyanoborohydride (101 mg, 1.75 mmol) in small portions.This mixture was stirred at room temperature for 40 h. The excess sodiumcyanoborohydride was destroyed by the addition of 6M HCl (to pH 1). Theresidue obtained after removal of volatiles was taken up in a minimalamount of water and extracted with ether. The aqueous layer was basifiedto pH 10 using solid KOH. This layer was then saturated with sodiumchloride and then extracted with EtOAc. Further analyses of the etherand the EtOAc layers suggest that the desired product resides the EtOAclayer. This material was used in the ensuing coupling reactions withoutfurther purification. Proton NMR spectrum show that the two pairs ofdiastereomers are obtained in ˜1:1 ratio, homogeneous by TLC, R_(f)=0.4in 95:5 CH₂Cl₂:MeOH. LC/MS m/e=318 (M+1). 400 MHz ¹H NMR (CDCl₃) δ 1.27,1.29 (2 d, J=7 Hz, 3H), 2.85 (m, 1H), 3.03 (m, 1H), 3.15 (m, 1H), 3.55(m, 1H), 4.85 (br, 2H), 5.00-5.18 (m, 2H), 7.0-7.2 (m, 9H).

REFERENCE EXAMPLE 61

2-Amino-4-(4-chlorophenyl)-3-cyclopentylbutane

Step A Methyl 3-(4-chlorophenyl)-2-cyclopentylpropanoate.

A mixture of methyl cyclopentylacetate (3.52 g, 25 mmol) and4-chlorobenzyl bromide (4.75 g, 23 mmol) was dissolved in 100 mL THF inan oven-dried flask. The solution was cooled to ˜40° C. and 23 mL 1MNaHMDS solution in hexanes was added slowly over an hour whilemaintaining the temperature at −40° C. The solution was then stirred foran additional 3 h at −40° C. The reaction was quenched at −40° C. withenough 10% citric acid solution to bring the pH to ˜3.5. The aqueouslayer was extracted with ether three times. The combined organics werewashed with water and dried over MgSO₄. The solvents were evaporatedunder reduced pressure and the crude material was purified by flashchromatography [Biotage 40 M, gradient elution using mixtures of hexaneand EtOAc (from 0-1% EtOAc)]. This provided a light brown oil, which isa 3:1 ratio of the title compound: methyl cyclopentylacetate based onthe methyl ester peak integrations. TLC of the desired product:R_(f)=0.34 in 20:1 hexane:EtOAc. The complete separation of the titlecompound from the starting material was not practical in this case, asthey had overlapping R_(f)'s on the TLC. Therefore, this mixture wascarried on to the next step.

Step B 3-(4-Chlorophenyl)-2-cyclopentylpropanioc acid.

The mixture of methyl esters from Step A (3.41 g , 14.48 mmol of methyl3-(4-chlorophenyl)-2-cyclopentylpropanoate—assuming 3:1 mixture obtainedin Step A.) was dissolved in 10 mL DMSO and 4 mL distilled water. Thenpowdered KOH (3.25 g, 57.92 mmol) was added and the solution was stirredovernight at room temperature. The next day the pH was brought to 2 with2 N HCl. The aqueous layer was extracted 3 times with ether. Thecombined organic extracts were dried over anhydrous sodium sulfate.Filtration and evaporation of volatiles provided the mixture of acids asan oil. 500 MHz ¹H NMR (CDCl₃): δ 1.28 (m, 2H), 1.64 (m, 6H), 2.06 (m,1H), 2.47 (m, 1H), 2.86 (t, 2H).

Step C 3-(4-Chlorophenyl)-2-cyclopentyl-N,O-dimethyl-propanamide.

The mixture of acids obtained in Step B (3.21 g, 14.48 mmol of thedesired acid—based on assumption of 3:1 mixture from Step B) wasdissolved in 75 mL CH₂Cl₂. While being stirred rigorously,N,O-dimethylhydroxylamine hydrochloride (1.56 g, 15.95 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (3.06 g, 16.0 mmol),diisopropylethylamine (5.56 mL, 31.90 mmol), and a catalytic amount of4-(dimethylaminopyridine) were added sequentially. Stirring wascontinued overnight at room temperature. The next day the reactionmixture was diluted with EtOAc, treated with water, and the phases wereseparated. The aqueous layer was re-extracted with EtOAc twice. Thecombined organic layers were washed with water three times and then withsaturated brine. The organic layer was dried over MgSO₄, filtered, andthe solvents were removed under reduced pressure. The crude material waspurified by flash chromatography [Biotage 40 M column, gradient elutionusing mixtures or hexanes and EtOAc (100:1 to 20:1] to provide the titlecompound cleanly as an oil. TLC R_(f)=0.31 (4:1 hexanes:EtOAc). LC/MSm/e 295.9 (M+1). 500 MHz ¹H NMR (CDCl₃): δ 1.27(m, 2H), 1.64 (m, 6H),1.97 (m, 1H), 2.13 (q, 1H), 2.81 (d, 1H), 2.97 (d, 1H), 3.07 (s, 3H),3.17 (s, 3H). LC/MS m/e 295.9 (M+1).

Step D 4-(4-Chlorophenyl)-3-cyclopentylbutan-2-one.

3-(4-Chlorophenyl)-2-cyclopentyl-N,O-dimethyl-propanamide (514 mg, 1.737mmol, obtained from Step C) was dissolved in 15 mL anhydrous THF andinjected into an oven dried flask under nitrogen. The solution wascooled to 0° C. and CH₃MgBr (1 M in ether) was added dropwise. The icebath was removed and the reaction was allowed to warm to roomtemperature and stirred for a total of 4 h. TLC indicated a nearlycomplete reaction. The reaction was quenched with enough 10% citric acidto bring the pH of the solution to 3. The aqueous layer was extracted 3times with ether and the extracts were dried over anhydrous MgSO₄. Thesolution was filtered and the solvents were removed under reducedpressure. The crude material was purified by flash chromatography (30 mLsilica; 100:1 to 50:1 hexanes:EtOAc) to provide 351 mg the titlecompound as an oil. TLC R_(f)=0.49 (4:1 hexanes:EtOAc). 500 MHz ¹H NMR(CDCl₃): δ 1.23 (m, 3H), 1.58 (m, 1H), 1.71 (m, 3H), 1.91 (s, 3H), 1.93(m, 1H), 2.05 (m, 1H), 2.68 (m, 1H), 2.84 (m, 2H).

Step E 2-Amino-4-(4-chlorophenyl)-3-cyclopentylbutane.

The title compound was prepared according to the procedure of ReferenceExample 45, Step D, except that4-(4-chlorophenyl)-3-cyclopentylbutan-2-one (obtained form Step D) wasused as the starting material. LC/MS m/e 251.9 (M+1); 500 MHz ¹H NMR(CDCl₃): δ 0.93 (m, 1H), 1.29 (q, 3H), 1.29 (m, 2H), 1.61 (m, 4H), 1.87(m, 3H), 2.62 (m, 1H), 2.80 (m, 1H), 3.26 and 3.48 (m, 1H).

2-Amino-4-(4-chlorophenyl)-3-ethyl-butane and2-amino-4-(4-chlorophenyl)-3-isopropyl-butane were also preparedaccording to the procedures described in Reference Example 61substituting the appropriate ester for methyl cyclopentylacetate in StepA.

REFERENCE EXAMPLE 62

2-Amino-3-(1-(1,2,3-triazolyl))-4-(4-chlorophenyl)butane

Step A Benzyl 2-(1-(1,2,3-triazolyl))acetate:

A mixture of 1,2,3-triazole (2.07 g, 30 mmol), benzyl bromoacetate (6.9g, 30 mmol), and diisopropylethylamine (5.1 mL, 30 mmol) in 40 mL CH₂Cl₂was stirred overnight at room temperature. This mixture was then dilutedwith ether until no further precipitate formed. The solid was filteredand washed with ether. The filtrate was concentrated and the residue waspurified on silica gel using 10% hexane in CH₂Cl₂ to give the titlecompound's isomer, benzyl 2-(2-(1,2,3-triazolyl)acetate as amorphoussolid. Further elution with a solvent mixture containing equal amountsof ether and CH₂Cl₂gave the title compound as amorphous solid. ¹H NMR(400 MHz, CDCl₃):δ 2.251 (s, 2H0, 7.267-7.390(m, 5H), 7.723(s, 1H),7.785(s,1H)

Step B 2-(1-(1,2,3-triazolyl)acetic acid:

Palladium hydroxide (20% on carbon, 800 mg) was added to a solution ofbenzyl 2-(1-(1,2,3-triazolyl))acetate (Step A, 8.68 g, 39.9 mmol) in 150mL MeOH and the mixture was hydrogenated overnight on a Parr shakerunder an atmosphere of hydrogen at room temperature and 45 psi. Thecatalyst was filtered through a bed of CELITE diatomaceous earth andwashed with MeOH. The filtrate was concentrated to give a solid, whichwas dried in vacuo at 50° C. for 36 h resulting in the title compound.¹H NMR (400 MHz, CD₃OD):δ 5.3 (s, 2H), 7.75 (s, 1H0, 8.016 (s, 1H).

Step C N-Methoxy-N-methyl-2-(1-(1,2,3-triazolyl))acetamide:

Oxalyl chloride (0.95 mL, 11 mmol) was added dropwise to a suspension of2-(1-1,2,3-triazolyl))acetic acid (Step B, 1.27 g, 10 mmol) in 10 mLCH₂Cl₂ containing 0.05 mL DMF. Vigorous effervescence was observed. Thismixture was stirred at room temperature for 4 h and cooled to −78° C. Asolution of NO-dimethylhydroxylamine hydrochloride (1.2 g, 13 mmol) anddiisopropylethyl amine (6.0 mL, 3.5 mmol) in 10 mL CH₂Cl₂ was addedslowly over 3 min. The mixture was then allowed to warm to roomtemperature and stirred overnight. The reaction mixture was then dilutedwith ether until no additional precipitate appeared. The solid wasfiltered and washed with ether. The filtrate was concentrated and theresidue was purified on silica gel using EtOAc as solvent to provide thetitle compound as amorphous solid. ¹H NMR (400 MHz, CDCl₃):δ 3.252 (s,3H0, 3.812 (s, 3H), 5.379 (s, 2H), 7.753 & 7.761 (s's, 2H).

Step DN-Methoxy-N-methyl-3-(4-chlorophenyl)-2-(1-(1,2,3-triazolyl))propionamide

Lithium hexamethyldisilazide (1 molar in THF, 8.4 mL, 8.4 mmol) wasadded dropwise to a solution ofN-methoxy-N-methyl-2-(1-(1,2,3-triazolyl))acetamide (Step C, 1.19 g, 7mmol) in 15 mL THF at −78° C. After additional 30 min stirring, asolution of 4-chlorobenzyl bromide (1.65 g, 8 mmol) in 5 mL THF wasadded dropwise. The mixture was allowed to warm to room temperature andstirred 5.5 h. This mixture was purified on silica gel using 40% EtOAcin hexane to give the title compound. ¹H NMR (400 MHz, CDCl₃): δ 3.186(s, 3H), 3.234-3.267 (m, 1H), 3.453-3.506 (m, 1H), 3.582 (s, 3H),6.145-6.188 (m, 1H), 7.048-7.279 (m, 4H), 7.726 (s, 1H), 7.954 (s, 1H).

Step E 2-Azido-3-(1-(1,2,3-triazolyl))-4-(4-chlorophenyl)butane:

The product of Step D,N-methoxy-N-methyl-3-(4-chlorophenyl)-2-(1-(1,2,3-triazolyl)propionamidewas converted to the title compound following the procedures describedin Reference Example 10, Step D-E and Reference Example 12, Step D. ¹HNMR (400 MHz, CDCl₃): δ 1.219-1.246 (d's 3H), 3.253-4.754 (m, 4H0,6.866-7.299 (d's, 4H), 7.313, 7.618, 7.63, & 7.706 (s's, 2H).

Step F 2-Amino-3-(1-(1,2,3-triazolyl))-4-(4-chlorophenyl)butane:

Platinum oxide (14 mg) was added to a solution of2-azido-3-(1-(1,2,3-triazolyl))-4-(4-chlorophenyl)butane (Step E, 138mg, 0.5 mmol) in 4 mL MeOH. This mixture was hydrogenated in anatmosphere of hydrogen using a hydrogen filled balloon for 3 h at roomtemperature. The catalyst was filtered through a bed of CELITEdiatomaceous earth and washed with MeOH. The filtrate was concentratedto give the title compound as oil. ¹H NMR (400 MHz, CDCl₃):δ 1.085-1.174(d's 3H), 3.220-3.361 (m, 2H), 3.517-3.563 (m, 1H), 4.379-4.431 (m, 1H),6.679-7.179 (d's, 4H), 7.297, 7.40, 7.592 & 7.607 (s's, 2H).

REFERENCE EXAMPLE 63

2-Amino-3-(1-(1,2,4-triazolyl)-4-(4-chlorophenyl)butane

The title compound was prepared according to the procedures described inReference Example 62 substituting 1,2,4-triazole for 1,2,3-triazole inStep A. The azide was separated by column chromatography on silica geleluted with 20% hexane in EtOAc.

REFERENCE EXAMPLE 64

N-[3-(4-Chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]aminehydrochloride (Diastereomer α)

Step A2-(N-tert-Butoxycarbonyl)amino-4-(4-chlorophenyl)-3-(3-methylphenyl)butane

A mixture of2-(N-tert-butoxycarbonyl)amino-3-(3-bromophenyl)-4-(4-chlorophenyl)butane(intermediate of Reference Example 47, 0.50 g, 1.1 mmol), tetramethyltin(0.41 g, 2.3 mmol), triphenylphosphine (0.12 g, 0.46 mmol), lithiumchloride (0.38 g, 9.1 mmol) and dichlorobis(triphenylphosphine)palladium(0.12 g, 0.17 mmol) in 20 mL anhydrous DMF was heated at 100° C. undernitrogen for 18 h. The reaction mixture was cooled to room temperature,and was partitioned between water (100 mL) and ether (100 mL). Theorganic layer was separated and the aqueous layer was extracted withether (100 mL). The combined extracts were dried over anhydrous MgSO₄,filtered and concentrated to dryness, and the residue was purified byflash column chromatography on silica gel eluted with 10% EtOAc inhexane to afford the title compound. ¹H NMR (400 MHz, CD₃OD): δ 7.2-6.8(m, 8H), 3.84 (m, 1H), 3.16 (m, 1H), 2.80-2.68 (m, 2H),2.24 (s, 3H),1.45 (s, 9H), 0.86 (d, 3H). LC-MS: m/e 396 (M+Na)⁺ (4.4 min).

Step B N-[3-(4-Chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]aminehydrochloride (Diastereomer α)

The title compound was prepared following the procedure described forReference Example 10, Step I. LC-MS: m/e 274 (M+H)⁺ (2.5 min).

REFERENCE EXAMPLE 65

N-[3-(4-Chlorophenyl)-2-(3-trifluoromethylphenyl)-1-methylpropyl]aminehydrochloride (Diastereomer α)

The title compound was prepared following the procedure described inReference Example 12 substituting fluorophenylacetic acid with3-trifluoromethylphenylacetic acid at Step A. LC-MS: m/e 328 (M+H)⁺ (2.6min).

REFERENCE EXAMPLE 66

N-[3-(5-Chloro-2-pyridyl)-2(S)-phenyl-1(S)-methylpropyl]aminehydrochloride (Diastereomer α)

Step A 5-Chloro-2-methylpyridine

A mixture of 2,5-dichloropyridine (15 g, 0.10 mol), tetramethyltin (15mL, 0.11 mol), and dichlorobis(triphenylphosphine)palladium (2.0 g, 2.8mmol) in 200 mL anhydrous DMF was heated at 110° C. under nitrogen for72 h. The reaction mixture was cooled to room temperature, and waspoured into a saturated solution of potassium fluoride (200 mL). Theresulting mixture was partitioned between water (500 mL) and ether (500mL). The organic layer was separated and the aqueous layer was extractedwith ether (200 mL). The combined extracts were dried over anhydrousMgSO₄, filtered and concentrated to dryness, and the residue waspurified by flash column chromatography on silica gel eluted with 2 to10% ether in hexane to afford the title compound. ¹H NMR (500 MHz,CD₃OD): δ 8.41 (d, 1H), 7.75 (dd, 1H), 7.30 (d, 1H), 2.53 (s, 3H).

Step B 4-(5-Chloro-2-pyridyl)-3(S)-phenyl-2(R)-butanol.

To a solution of 5-chloro-2-methylpyridine (Step A, 1.1 g, 8.7 mmol) in15 mL anhydrous ether was added phenyl lithium (1.8 M incyclohexane/ether, 7.2 mL, 13 mmol) at 0° C., and the reaction wasstirred at room temperature for 30 min. The resulting mixture was cooledback to 0° C., and was added (1R,2R)-1-phenylpropylene oxide (2.3 g, 17mmol), and the reaction was allowed to warm to room temperatureovernight. The reaction mixture was partitioned between EtOAc (100 mL)and water (100 mL). The organic layer was separated and the aqueouslayer extracted with EtOAc (2×100 mL). The combined organic extractswere dried over anhydrous MgSO₄, filtered, and concentrated to dryness,and the residue was purified by flash column chromatography on silicagel eluted with 10 to 40% EtOAc in hexane to afford the title compound.¹H NMR (500 MHz, CD₃OD): δ 8.28 (d, 1H), 7.59 (dd, 1H), 7.25-7.12 (m,5H), 7.05 (d, 1H), 4.03 (m, 1H), 3.29 (dd, 1H), 3.19 (dd, 1H), 3.12 (m,1H), 1.12 (d, 3H).

Step C 2(S)-Azido-4-(5-chloro-2-pyridyl)-3(S)-phenylbutane

To a mixture of 4-(5-chloro-2-pyridyl)-3-phenyl-2-butanol (Step B, 0.24g, 0.92 mmol), triphenylphosphine (1.5 g, 1.4 mmol) anddiphenylphosphoryl azide (0.30 mL, 1.4 mmol) in 5 mL anhydrous THF wasadded diethylazodicarboxylate (0.24 mL, 1.4 mmol). After stirring atroom temperature overnight, the resulting mixture was concentrated withsilica gel (10 g) and the residue was loaded onto a silica gel column.Elution with 5 to 15% EtOAc in hexane afforded the title compound. ¹HNMR (500 MHz, CD₃OD): δ 8.35 (d, 1H), 7.52 (dd, 1H), 7.25-7.05 (m, 5H),6.95 (d, 1H), 3.81 (m, 1H), 3.48 (m, 1H), 3.15-3.05 (m, 2H), 1.14 (d,3H).

Step D N-[3-(5-Chloro-2-pyridyl)-2(S)-phenyl-1(S)-methylpropyl]amine,Hydrochloride

The product of Step C (0.20 g, 0.70 mmol) was converted to the titlecompound following the procedure described in Reference Example 10,Steps H-I, except hydrogen chloride in dioxane (4 M) was used in placeof hydrogen chloride in EtOAc. ¹H NMR (500 MHz, CD₃OD): δ 8.75 (d, 1H),8.19 (dd, 1H), 7.55 (d, 1H), 7.4-7.2 (m, 5H), 3.78 (m, 1H), 3.62 (dd,1H), 3.48 (m, 1H), 3.43 (dd, 1H), 3H). LC-MS: m/e 261 (M+H)⁺ (2.2 min).

REFERENCE EXAMPLE 67

N-[2-(3-Bromophenyl)-3-(5-chloro-2-pyridyl)-1-methylpropyl]aminehydrochloride (Diastereomer α)

Step A 3-Bromophenylacetone

To a solution of N-methoxy-N-methylacetamide (10 g, 100 mmol) in 100 mLanhydrous ether at 0° C. was added 3-bromobenzylmagnesium bromide (0.25M in ether, 200 mL, 50 mmol). The reaction was allowed to warm to roomtemperature overnight and was quenched by the addition of saturatedammonium chloride (100 mL). The organic layer was separated and theaqueous layer was extracted with hexane (100 mL). The combined extractswere dried over anhydrous MgSO₄, filtered and concentrated to dryness toafford the title compound. ¹H NMR (500 MHz, CD₃OD): δ 7.45-7.40 (m, 2H),7.26 (t, 1H), 7.19 (d, 1H), 2.20 (s, 3H).

Step B 3-(3-Bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanone

A suspension of 5-chloro-2-methylpyridine (Reference Example 66, Step A,6.4 g, 50 mmol) and N-bromosuccinimide (12.5 g, 70 mmol) in 100 mLcarbon tetrachloride was heated to gentle reflux (bath temperature 90°C.), and 2,2′-azobisisobutyronitrile (0.74 g) was added in severalportions over 30 min. After stirring at this temperature for 5 h, thereaction mixture was concentrated. The resulting slurry was diluted withEtOAc (100 mL) and was washed with water (100 mL), saturated aqueoussodium bicarbonate/saturated aqueous sodium thiosulfate, and brine. Theorganic solution was dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness, and the residue was purified by flash columnchromatography on silica gel eluted with 2 to 15% ether in CH₂Cl₂/hexane(1:1) to afford 2-bromomethyl-5-chloropyridine (6.0 g, 60%), which wasused immediately for the ensuing reaction. Thus, to a vigorously stirredsolution of 2-bromomethyl-5-chloropyridine (6.0 g, 29 mmol) and3-bromophenyl acetone (Step A, 6.0 g, 28 mmol) and tetrabutylammoniumiodide (20 mg) in 30 mL CH₂Cl₂ at −78° C. was added cesium hydroxidemonohydrate (10 g, 60 mmol), and the reaction was allowed to slowly warmto room temperate overnight. The reaction mixture was partitionedbetween EtOAc (100 mL) and water (100 mL). The organic layer wasseparated and the aqueous layer extracted with EtOAc (2×100 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered, and concentrated to dryness, and the residue was purified byflash column chromatography on silica gel eluted with 5 to 40% EtOAc inhexane to afford the title compound. ¹H NMR (500 MHz, CD₃OD): δ 8.44 (d,1H), 7.66 (dd, 1H), 7.46-7.41 (m, 2H), 7.24 (t, 1H), 7.22 (d, 1H), 7.15(d, 1h), 4.42 (dd, 1H), 3.54 (dd, 1H), 3.07 (dd, 1H), 2.12 (s, 3H).LC-MS: m/e 338 (M+H)⁺ (3.0 min).

Step C 3-(3-Bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanol

To a solution of 3-(3-bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanone(Step B, 6.7 g, 20 mmol) in 50 mL anhydrous THF at −78° C. was addedlithium tri(sec-butyl)borohydride (1.0 M in THF, 30 mL, 30 mmol), andthe reaction was allowed to warm to room temperature overnight. Thereaction was cooled to 0° C., and was carefully added 2 M hydrochloricacid (50 mL), and the resulting mixture was partitioned between hexane(200 mL) and water (200 mL). The aqueous layer was separated and theorganic layer extracted with 2 M hydrochloric acid (2×100 mL). Thecombined aqueous extracts were neutralized with 5 N aqueous sodiumhydroxide (pH>12), and was extracted with EtOAc (2×200 mL). The combinedextracts were dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness to afford the title compound.

Step D N-[2-(3-Bromophenyl)-3-(5-chloro-2-pyridyl)-1-methylpropyl]amine,Hydrochloride

The product of Step C (5.9 g, 17 mmol) was converted to the titlecompound following the procedure described in Reference Example 66,Steps C-D. LC-MS: m/e 338 (M+H)⁺ (2.3 min).

REFERENCE EXAMPLE 68

N-[3-(5-Chloro-2-pyridyl)-2-(3-chlorophenyl)-1-methylpropyl]aminehydrochloride (Diastereomer α)

The title compound was prepared following the procedure described inReference Example 49 substituting2-(N-tert-butoxycarbonyl)amino-3-bromophenyl-4-(4-chlorophenyl)butanewith2-(N-tert-butoxycarbonyl)amino-3-bromophenyl-4-(5-chloro-2-pyridyl)butane(intermediate of Reference Example 67, Step D) at Step A. LC-MS: m/e 295(M+H)⁺ (2.0 min).

REFERENCE EXAMPLE 69

N-[2-(5-Bromo-2-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]aminehydrochloride (Diastereomer α)

Step A 5-Bromo-3-pyridylacetone

A mixture of 3,5-dibromopyridine (50 g, 0.21 mol), isopropenyl acetate(26 mL, 0.23 mmol), tris(dibenzylideneacetone)dipalladium (1.0 g, 1.1mmol) and 2-(diphenylphosphino)-2′(N,N-dimethylamino)biphenyl (1.6 g,4.2 mmol) in 400 mL toluene was heated at 100° C. under nitrogen for 2h. The reaction mixture was cooled to room temperature, and wasconcentrated to about 100 mL. The resulting mixture was loaded onto asilica gel column, which was eluted with 0 to 60% EtOAc in hexane toafford the title compound. ¹H NMR (500 MHz, CD₃OD): δ 8.54 (br s, 1H),8.33 (br s, 1H), 7.88 (br s, 1H), 3.90 (s, 2H), 2.25 (s, 3H).

Step B 3-(5-Bromo-3-pyridyl)-4-(4-chlorophenyl)-2-butanol

The title compound was prepared following the procedure described inReference Example 67, Step B-C, substituting2-bromomethyl-5-chloropyridine with 4-chlorobenzyl chloride and3-bromophenylaceatone with 5-bromo-3-pyridylacetone (Step A). ¹H NMR(500 MHz, CD₃OD): δ 8.43 (d, 1H), 8.24 (d, 1H), 7.98 (dd, 1H), 7.17 (d,2H), 7.07 (d, 2H), 4.04 (m, 1H), 3.16 (dd, 1H), 3.0-2.9 (m, 2H), 1.04(d, 3H).

Step C N-[2-(5-Bromo-3-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]aminehydrochloride (Diastereomer α)

The title compound was prepared following the procedure described forReference Example 11, Step B. LC-MS: m/e 339 (M+H)⁺ (2.5 min).

REFERENCE EXAMPLE 70

N-[2-(5-Bromo-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

The title compound was prepared following the procedure described forReference Example 69 substituting 4-chlorobenzyl chloride with4-flurobenzyl chloride at Step B. LC-MS: m/e 323 (M+H)⁺ (2.3 min).

REFERENCE EXAMPLE 71

N-[3-(4-Chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

Step A 5-Cyano-3-pyridylacetone

The title compound was prepared following the procedure described forReference Example 69 substituting 3,5-dibromopyridine with5-bromonicotinonitrile (5-bromo-3-cyanopyridine) at Step A. ¹H NMR (400MHz, CD₃OD): δ 8.89 (d, 1H), 8.60 (d, 1H), 8.02 (t, 1H), 3.98 (s, 2H),2.24 (s, 3H).

Step B N-[3-(4-Chlorophenyl)-2-(5-cyano-2-pyridyl)-1-methylpropyl]amineHydrochloride (Diastereomer α/β 5:1)

The title compound was prepared following the procedure described forReference Example 19 substituting 3-pyridylacetone with5-cyano-3-pyridylacetone (Step A). LC-MS: m/e 286 (M+H)⁺ (1.9 min).

REFERENCE EXAMPLE 72

N-[2-(5-Cyano-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

The title compound was prepared following the procedure described forReference Example 71 substituting 4-chlorobenzyl chloride with4-fluorobenzyl chloride at Step B. LC-MS: m/e 270 (M+H)⁺ (2.2 min).

REFERENCE EXAMPLE 73

N-[2-(5-Cyano-3-pyridyl)-3-(3,4-difluorophenyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

The title compound was prepared following the procedure described forReference Example 72 substituting 4-fluorobenzyl chloride with3,4-difluorobenzyl chloride at Step B. LC-MS: m/e 288 (M+H)⁺ (2.3 min).

REFERENCE EXAMPLE 74

N-[3-(3-Chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

The title compound was prepared following the procedure described forReference Example 72 substituting 4-fluorobenzyl chloride with3-chlorobenzyl chloride at Step B. LC-MS: m/e 286 (M+H)⁺ (2.4 min).

REFERENCE EXAMPLE 75

N-[3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

Step A 5-Chloro-3-pyridylacetone

The title compound was prepared following the procedure described forReference Example 69 substituting 3,5-dibromopyridine with3,5-dichloropyrdine and2-(diphenylphosphino)-2′(N,N-dimethylamino)biphenyl with2-(di-t-butylphosphino) biphenyl at Step A. ¹H NMR (500 MHz, CD₃OD): δ8.42 (d, 1H), 8.27 (d, 1H), 7.73 (dd, 1H), 3.90 (s, 2H), 2.25 (s, 3H).

Step B N-[3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

The title compound was prepared following the procedure described forReference Example 69, Step B-C substituting 5-bromo-3-pyridylacetonewith 5-chloro-3-pyridylacetone at Step B. LC-MS: m/e 295 (M+H)⁺ (1.9min).

REFERENCE EXAMPLE 76

N-[2-(5-Chloro-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

The title compound was prepared following the procedure described forReference Example 75 substituting 4-chlorobenzyl chloride with4-fluorobenzyl chloride at Step B. LC-MS: m/e 279 (M+H)⁺ (2.3 min).

REFERENCE EXAMPLE 77

2-Amino-3-(5-chloro-3-pyridyl)-5-methylhane, Hydrochloride Salt(Diastereomer α/β 6:1)

The title compound was prepared following the procedure described forReference Example 75 substituting 4-chlorobenzyl chloride with1-iodo-2-methylpropane at Step B. LC-MS: m/e 227 (M+H)⁺ (2.2 min).

REFERENCE EXAMPLE 78

N-[2-(5-Chloro-3-pyridyl)-3-cyclobutyl-1-methylpropyl]amineHydrochloride (Diastereomer α/β 6:1)

The title compound was prepared following the procedure described forReference Example 75 substituting 4-chlorobenzyl chloride with(bromomethyl)cyclobutane at Step B. LC-MS: m/e 239 (M+H)⁺ (2.3 min).

REFERENCE EXAMPLE 79

N-[3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

Step A 3-Cyanophenylacetone

The title compound was prepared following the procedure described forReference Example 69 substituting 3,5-dibromopyridine with3-bromobenzonitrile and2-(diphenylphosphino)-2′-(N,N-dimethylamino)biphenyl with2-(dicyclohexylphosphine)-2′-(N,N-dimethylamino)biphenyl at Step A. ¹HNMR (500 MHz, CD₃OD): δ 7.6 (m, 1H), 7.56 (br s, 1H), 7.50-7.48 (m, 2H),3.88 (s, 2H),2.21 (s, 3H).

Step B N-[3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

The title compound was prepared following the procedure described forReference Example 69 substituting 5-bromo-3-pyridylacetone with3-canophenylacetone at Step B. LC-MS: m/e 285 (M+H)⁺ (2.2 min).

REFERENCE EXAMPLE 80

N-[3-(4-Chlorophenyl)-2-(5-fluoro-3-pyridyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

Step A 5-fluoro-3-pyridylacetone

The title compound was prepared following the procedure described forReference Example 69 substituting 3,5-dibromopyridine with3-fluoro-5-trifluoromethanesulfonyloxypyridine (prepared form3-fluoro-5-hydroxypyrdine and triflic anhydride) and2-(diphenylphosphino)-2′(N,N-dimethylamino)biphenyl with2-(dicyclohexylphosphino)-2′(N,N-dimethylamino)biphenyl at Step A. ¹HNMR (500 MHz, CD₃OD): δ 8.34 (d, 1H), 8.22 (br s, 1H), 7.50 (ddd, 1H),3.93 (s, 2H), 2.25 (s, 3H).

Step B N-[3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

The title compound was prepared following the procedure described forReference Example 69, Step B-C substituting 5-bromo-3-pyridylacetonewith 5-fluoro-3-pyridylacetone at Step B. LC-MS: m/e 279 (M+H)⁺ (2.4min).

REFERENCE EXAMPLE 81

N-[3-(4-Chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

The title compound was prepared following the procedure described forReference Example 64 substituting2-(N-tert-butoxycarbonyl)amino-3-(3-bromophenyl)-4-(4-chlorophenyl)butanewith2-(N-tert-butoxycarbonyl)amino-3-(5-bromo-3-pyridyl)-4-(4-chlorophenyl)butane(intermediate ot Reference Example 69, Step B) at Step A. LC-MS: m/e 275(M+H)⁺ (1.3 min).

REFERENCE EXAMPLE 82

2-Methyl-2-(3-trifluoromethylphenyloxy)propionic Acid

The title compound was prepared following the same procedure describedfor Reference Example 27. ¹H NMR (500 MHz, CD₃OD): δ 7.45 (t, 1H), 7.28(d, 1H), 7.16 (s, 1H), 7.13 (d, 1H), 1.62 (s, 6H).

REFERENCE EXAMPLE 83

2-Methyl-2-(3-cyanophenyloxy)propionic Acid

The title compound was prepared following the same procedure describedfor Reference Example 27. ¹H NMR (500 MHz, CD₃OD): δ 7.63 (d, 2H), 6.97(d, 2H), 1.65 (s, 6H).

REFERENCE EXAMPLE 84

2-Methyl-2-(6-chloromethyl-2-pyridyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 54 substituting 5-chloro-2-hydroxpyridine with6-chloro-2-hydroxpyridine at Step A. ¹H NMR (500 MHz, CD₃OD): δ 7.64 (t,1H), 6.95 (d, 1H), 6.72 (d, 1H), 1.65 (s, 6H). LC-MS: m/e 216 (M+H)⁺(2.4 min).

REFERENCE EXAMPLE 85

2-Methyl-2-(2-pyrimidyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 54 substituting 5-chloro-2-hydroxpyridine with2-hydroxpyrimidine at Step A. ¹H NMR (500 MHz, CD₃OD): δ 8.53 (d, 2H),7.09 (t, 1H), 1.74 (s, 6H).

REFERENCE EXAMPLE 86

2-Methyl-2-(5-chloro-2-pyrimidyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 54 substituting 5-chloro-2-hydroxpyridine with5-chloro-2-hydroxpyrimidine at Step A. ¹H NMR (500 MHz, CD₃OD): δ 8.55(s, 2H), 1.73 (s, 6H).

REFERENCE EXAMPLE 87

2-Methyl-2-(4-trifluoromethyl-2-pyrimidyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 54 substituting 5-chloro-2-hydroxpyridine with4-trifluoromethyl-2-hydroxpyrimidine at Step A. ¹H NMR (500 MHz, CD₃OD):δ 8.85 (d, 1H), 7.48 (d, 1H), 1.76 (s, 6H).

REFERENCE EXAMPLE 88

2-Methyl-2-(4-trifluoromethyl-2-pyridyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 54 substituting 5-chloro-2-hydroxpyridine with4-trifluoromethyl-2-hydroxpyridine at Step A. ¹H NMR (500 MHz, CD₃OD): δ8.30 (d, 1H), 7.18 (d, 1H), 7.05 (s, 1H), 1.71 (s, 6H).

REFERENCE EXAMPLE 89

2-Methyl-2-(4-pyrimidyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 54 substituting 5-chloro-2-hydroxpyridine with4-hydroxpyrimidine at Step A. ¹H NMR (500 MHz, CD₃OD): δ 8.67 (s, 1H),8.47 (d, 1H), 6.91 (d, 1H), 1.73 (s, 6H).

REFERENCE EXAMPLE 90

2-Methyl-2-(6-trifluoromethyl-4-pyrimidyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 54 substituting 5-chloro-2-hydroxpyridine with6-trifluoromethyl-4-hydroxpyrimidine at Step A. ¹H NMR (500 MHz, CD₃OD):δ 8.81 (s, 1H), 7.28 (s, 1H), 1.75 (s, 6H). LC-MS: m/e 251 (M+H)⁺ (2.1min).

REFERENCE EXAMPLE 91

2-Methyl-2-(4-trifluoromethyl-2-pyridyloxy)propionic Acid

Step A 2-(4-Trifluoromethyl-2-pyridyloxy)propionic Acid

To a suspension of lithium lactate (7.8 g, 81 mmol) in 100 mL anhydrousDMF was added sodium hydride (60% dispersion in mineral oil, 3.2 g, 80mmol). After stirring at room temperature for 30 min,2-chloro-4-trifluromethylpyridine (10 g, 55 mmol) was added, and themixture was heated at 100° C. overnight. The reaction was cooled to roomtemperature, poured into 500 mL water, and was washed with hexane (200mL). The aqueous solution was acidified with concentrated hydrochloricacid (pH>2), and was extracted with ether (2×500 mL). The combinedextracts were washed with water and brine, dried over anhydrous sodiumsulfate, filtered and concentrated to dryness to give the titlecompound.

Step B Methyl 2-Methyl-2-(4-trifluoromethyl-2-pyridyloxy)propionate

To a solution of 2-(4-trifluoromethyl-2-pyridyloxy)propionic acid (StepA, 15 g, 55 mol) in 100 mL CH₂Cl₂ and 100 mL MeOH at 0° C. was addedtrimethylsilydiazomethane (2 M solution in hexane) until a yellow colorpersisted. After stirring at room temperature for 15 min, the reactionmixture was concentrated to dryness, and the residue was purified byflash chromatography on silica gel eluted with 0 to 10% EtOAc in hexaneto give methyl 2-(4-trifluoromethyl-2-pyridyloxy)propionate (10 g),which was used immediately for methylation following the proceduredescribed in Reference Example 39, Step B substituting ethyl iodide withmethyl iodide. ¹H NMR (500 MHz, CD₃OD): δ 8.25 (d, 1H), 7.18 (d, 1H),7.15 (s, 1H), 3.65 (s, 3H), 1.65 (s, 6H).

Step C 2-Methyl-2-(4-trifluoromethyl-2-pyridyloxy)propionic Acid

To a solution of methyl2-methyl-2-(4-trifluoromethyl-2-pyridyloxy)propionate (Step B, 7.5 g, 29mol) in 50 mL MeOH, 50 mL THF and 50 mL water was added sodium hydroxide(2.3 g, 57 mmol). After stirring at 50° C. for 5 h, the reaction mixturewas partially concentrated, and was added 2 M hydrochloric acid to pH>2.The resulting mixture was extracted with EtOAc (2×200 mL), and thecombined extracts were dried over anhydrous sodium sulfate, filtered,and concentrated to dryness to afford the title compound. ¹H NMR (500MHz, CD₃OD): δ 8.28 (d, 1H), 7.17 (d, 1H), 7.05 (s, 1H), 1.70 (s, 6H).

REFERENCE EXAMPLE 92

2-Methyl-2-(5-trifluoromethyl-2-pyridyloxy)propionic Acid

The title compound was prepared following the procedure described inReference Example 91, Step A with 1.5 extra equivalent of sodium hydridesubstituting lithium lactate with hydroxyisobutyric acid and2-chloro-4-trifluoromethylpyridine 2-chloro-5-trifluoromethylpyridine.¹H NMR (500 MHz, CD₃OD): δ 8.38 (br, 1H), 7.94 (dd, 1H), 6.93 (d, 1H),1.69 (s, 6H).

REFERENCE EXAMPLE 93

N-[2-(3-Bromo-5-fluorophenyl)-3-(4-Chlorophenyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

Step A 3-Bromo-5-fluorophenylacetone

The title compound was prepared following the procedure described forReference Example 69 substituting 3,5-dibromopyridine with1,3-dibromo-5-fluorobenzene and2-(diphenylphosphino)-2′-(N,N-dimethylamino)biphenyl with1,1′-bis(diphenylphosphino)ferrocene at Step A. ¹H NMR (500 MHz, CD₃OD):δ 7.23 (d, 1H), 7.22 (s, 1H), 6.96 (d, 1H), 3.81 (s, 2H), 2.20 (s, 3H).

Step BN-[2-(3-Bromo-5-fluorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

The title compound was prepared following the procedure described forReference Example 69, Step B substituting 5-bromo-3-pyridylacetone with3-bromo-5-fluorophenylacetone (Step A). LC-MS: m/e 356 (M+H)⁺ (2.9 min).

REFERENCE EXAMPLE 94

N-[2-(3-Bromo-5-fluorophenyl)-3-(4-fluorophenyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

The title compound was prepared following the procedure described forReference Example 93 substituting 4-chlorobenzyl chloride with4-fluorobenzyl chloride at Step B. LC-MS: m/e 340 (M+H)⁺ (2.8 min).

REFERENCE EXAMPLE 95

2(R)-(5-Trifluoromethyl-2-pyridyloxy)propionic Acid

Step A 2(R)-(5-trifluoromethyl-2-pyridyloxy)propionate

The title compound was prepared following the procedure described inReference Example 39, Step A substituting 2-hydroxypyridine with5-trifluoromethyl-2-hydroxypyridine and benzyl lactate with benzyl(S)-lactate. LC-MS: m/e 326 (M+H⁺ (3.1 min).

Step B 2(R)-(5-trifluoromethyl-2-pyridyloxy)propionic Acid

The title compound was prepared following the procedure described inReference Example 39, Step C substituting benzyl2-(2-pyridyloxy)-2-methylbutanoate with2(R)-(5-trifluoromethyl-2-pyridyloxy)propionate (Step A). ¹H NMR (500MHz, CD₃OD): δ 8.70 (s, 1H), 7.67 (d, 1H), 6.63 (d, 1H), 5.30 (q, 1H),1.67 (d, 3H).

REFERENCE EXAMPLE 962-Methyl-2-(5-trifluoromethyl-2-pyridyloxy)propionic Acid

Two nitrogen flushed, 12 L 3-necked round bottom flasks, each fittedwith a thermometer and a reflux condenser were charged with KHMDS in THF(0.91 M, 3.52 L each, 3.205 mol, 1.5 eq). The solutions were cooled to−70° C. and stirred magnetically. Ethyl-2-hydroxyisobutyrate (98%) (463mL, 447 g, 3.38 mol) was added to each flask over 30 min, keeping thereaction temperature below −62° C. After 10 min2-chloro-5-trifluormethylpyridine (388 g, 2.14 mol) was added to eachflask in one portion. The cooling bath was removed and the reactionswere allowed to warm to 20° C. overnight (ca 16 hr.). The reactions weremonitored by TLC (silica, 90/10 Hex/EtOAc) and HPLC:

Sodium hydroxide (1.36 L, 5N) was added to each reaction flask and thereactions were refluxed overnight (ca 22 hr). The reactions wereconcentrated together on a rotary evaporator to remove the THF. To theconcentrate was added water (4 L) and the solution extracted withn-heptane (2×4 L). The aqueous layer was added over 10 min to 2N HCl (9L, 18 mol) with stirring. The resulting suspension was aged for 30 min(temperature 30° C.) then filtered. The cake was washed with water (3×2L), and air-dried to a damp tan solid.

The material was dissolved in n-heptane (4 L) at 65° C. IPAc (1 L) andDARCO KB (40 g, 100 mesh) were added. The mixture was stirrer for 15min, filtered through CELITE diatomaceous earth, and the cake washedwith 4:1 heptane/IPAc (3×500 mL). The filtrate was concentrated to ca. 2L affording a white suspension. The slurry was flushed with heptane (2×3L) and concentrated to ca. 3 L. The resulting white suspension wascooled to 0° C. and aged 1 hr. The product was filtered and the cakewashed with cold heptane (1 L) to provide the title compound as whitecrystalline material. HPLC Column: YMC Combiscreen Pro C18, 50×4.6 mm;Mobile phase: A 0.1% TFA in H₂O; B CH₃CN. Gradient: 90/10 A/B to 10/90A/B in 4 min. Flow rate: 4 mL/min. Detection: 254 nm. R_(t)2-chloro-5-trifluormethylpyridine 2.1 min. R_(t)2-ethoxy-5-trifluoromethylpyridine 2.9 min. R_(t) Product Ester 3.1 min.R_(t) Final Acid 2.05 min

REFERENCE EXAMPLE 97

2-Amino-3-indolin-N-yl-4(4-chloro)phenylbutane

Step A. Ethyl 3-(4-chlorophenyl)-2-indolin-N-ylpropanoate.

In an oven-dried flask under an atmosphere of nitrogen, 1.1 g LiOH.H₂O(26.25 mmol) in DMF (20 mL) was added to a stirring suspension of 4angstrom molecular sieves. After 30 minutes of stirring at roomtemperature 2.8 mL (25 mmol) indoline was added dropwise. After one hourat room temperature 2.9 mL (26.25 mmol) Ethyl bromoacetate was addeddropwise. After 1.5 h the solid material was filtered and the residuewas washed with copious amounts of EtOAc. The organics were washed 3times with water and the organic material was dried over MgSO₄. Thesolvents were evaporated under reduced pressure. The crude material wasthen dissolved in 75 mL anhydrous THF, charged into an oven dried roundbottom under an atmosphere of nitrogen, cooled to −78° C., and thentreated with 26.25 mL a 1M solution of NaHMDS. The solution was allowedto stir for 30 minutes at −78° C. after which the enolate was quenchedwith 5.4 g (26.25 mmol) of parachlorobenzyl bromide (solution in 25 mLanhydrous THF). The reaction was allowed to warm to room temperatureovernight. The next day the reaction was quenched with water. Theaqueous layer was extracted with 3 large portions of EtOAc. The combinedorganics were dried over MgSO₄. The solvents were removed under reducedpressure and the residue was purified by flash chromatography whichyielded the title compound as a yellow oil. LC/MS m/e=331 (M+1). TLCR_(f)=0.22 (20:1 hexanes:EtOAc). ¹H NMR (500 MHz, CDCl₃): δ 1.11 (t,J=3.55 Hz, 3H), 2.96 (m, 2H), 3.06 (m, 1H), 3.25 (m, 1H), 3.60 (t, 2H),4.07 (m, 2H), 4.36 (t, J=3.75 Hz, 1H).

Step B. N,O-dimethyl-3-(4-chlorophenyl)-2-indolin-N-ylpropanamide.

In an oven-dried flask under an atmosphere of nitrogen, 11.75 mL 1 Msolution of (CH₃)₂AlCl in CH₂Cl₂ was added via addition funnel to astirring suspension of 1.15 g (11.75 mmol) N,O-dimethylhydroxylaminehydrochloride at 0° C. After warming to room temperature a solution of970 mg (2.94 mmol) of Ethyl 3-(4-chlorophenyl)-2-indolinylpropanoate in10 mL was added via addition funnel. After stirring at room temperaturefor 5 h, 35 mL pH=8 phospate buffer solution was added and the resultingsolution was stirred vigorously for 30 minutes. The phases wereseparated and the aqueous layer was extracted 2 times with chloroform.The combined organics were washed with water and then dried over MgSO₄.A brown oil was collected. The crude material was carried on to the nextstep. ). TLC R_(f)=0.12 (10:1 hexanes:EtOAc). ¹H NMR (500 MHz, CDCl₃): δ2.83 (m, 1H), 2.97 (m, 2H), 3.13 (s, 3H), 3.34 (m, 1H), 3.45 (s, 3H),3.61 (m, 2H), 4.87 (b, 1H), 6.54 (d, 1H), 6.66 (t, J=7.1 Hz, 1H), 7.07(t, J=7.1 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 7.24 (d, J=8.5 Hz, 2H)

Step C. 4-(4-chlorophenyl)-3-indolin-N-ylbutan-2-one.

In an oven dried flask under an atmosphere of nitrogen, 2.8 mL 1 Msolution of CH₃MgBr in THF was added dropwise to a stirring solution ofN,O-dimethyl-3-(4-chlorophenyl)-2-indolinylpropanamide (965 mg) in 25 mLanhydrous THF. The solution was stirred for 4 h while being allowed towarm to room temperature. Then approximately 20 mL water were added. Thesolution was extract three times with 50 mL ether. The combined extractswere dried over MgSO₄. The solvents were removed under reduced pressureyielding a brown oil which was carried on to the next step withoutpurification. LC/MS m/e=301 (M+1). TLC R_(f)=0.5 (4:1 hexanes:EtOAc). ¹HNMR (500 MHz, CDCl₃): δ 2.14 (s, 3H), 2.81 (dd, J=14.6, 6.6 Hz, 1H),2.97 (t, J=8.5 Hz, 2H), 3.26 (m, 2H), 3.5 (m, 1H), 4.21 (dd, J=6.6, 6.6Hz), 6.39 (d, J=8 Hz, 1H), 6.66 (dd, J=7, 7 Hz, 1H), 7.07 (m, 2H), 7.13(d, J=8.5 Hz), 7.22 (d, J=8.3 Hz).

Step D. 4-(4-chlorophenyl)-3-indolin-N-ylbutan-2-one Methoxime.

A solution of 472 mg (1.573 mmol) of the product of Step C and 263 mg(3.147 mmol) of methoxylamine hydrochloride in anhydrous ethanol wastreated with 255 μL (3.147 mmol) of pyridine. The solution was stirredfor 2 h at room temperature. Solvent was removed under reduced pressureand the residue was partitioned between water and ether. The water wasextracted with ether again. The extracts were then combined and driedover MgSO₄, filtered and concentrate to obtain crude material. obtained.Both the E and Z isomers were carried onto the next step. LC/MS m/e=330(M+1). TLC R_(f)=0.77 and 0.65 (4:1 hexanes:EtOAc). ¹H NMR (500 MHz,CDCl₃): δ 1.78 (2s, 1H), 2.88 (dd, J=6.2, 13.8 Hz, 1H), 2.95 (m, 2H),3.30 (m, 2H), 3.45 (m, 1H), 3.75 and 3.89 (2s, 3H), 4.21 (dd, J=6.9, 7.8Hz, 1H), 6.28 and 6.47 (2d, J=8.1, 1H), 6.61 (m, 1H), 7.02 (m, 2H), 7.22(m, 4H).

Step E. 2-Amino-3-indolin-N-yl-4(4-chloro)phenylbutane

In an oven-dried flask equipped with a water condenser under anatmosphere of nitrogen, a solution of 301 mg (0.914 mmol)4-(4-chlorophenyl)-3-indolinylbutan-2-one methoxime in 1.5 mL anhydrousTHF was treated with 3.7 mL (3.7 mmol) of 1M BH₃.THF at roomtemperature. The solution was then heated to 75° C. for 2 days. Thesolution was then cooled to 0° C. and treated with chips of ice untilbubbling subsided. 500 μL of 20% KOH were then added and the solutionwas heated at 45° C. for 2 h. The solution was then cooled to roomtemperature and extracted with ether 3×. The combined extracts weredried over MgSO₄, filtered, and concentrated to afford crude amine whichwas used in the next experiment without further purification. LC/MSm/e=302 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 1.13, 1.14 (2d, J=6.5 Hz, 1H),1.55-1.60 (m, 2H), 2.80-3.10 (m, 4H), 3.30-3.60 (m, 2H), 6.348 and 6.38(2d, J=7.9 Hz, 1H), 6.50-6.78 (m, 2H), 6.95-7.24 (m, 5H)

REFERENCE EXAMPLE 98

2-Amino-3-indol-N-yl-4(4-chloro)phenylbutane

This compound was prepared in an analogous manner to Reference Example97 except that during Step A, sodium hydride was used as the baseinstead of the lithium hydroxide monohydrate/molecular sievescombination. LC/MS: calculated for C₁₈H₁₉ClN₂ 299, observed m/e 300(M+H)⁺ (2.4 min).

REFERENCE EXAMPLE 99

2-Amino-3-(N-methyl,N-phenyl)amino-4(4-chloro)phenylbutane

This compound was prepared in an analogous manner to Reference Example97. LC/MS: calculated for C₁₇H₂₁ClN₂ 289, observed m/e 290 (M+H)⁺ (2.4min).

REFERENCE EXAMPLE 100

2-Amino-3-(7-azaindol-N-yl)-4(4-chloro)phenylbutane

This compound was prepared in an analogous manner to Reference Example97. LC/MS: calculated for C₁₇H₁₈ClN₃ 300, observed m/e 301 (M+H)⁺ (2.7min).

REFERENCE EXAMPLE 101

2-Amine-3-(benzisoxazol-3-yl)-4-(4-chloro)phenylbutane

This compound was prepared in an analogous manner to Reference Example97 except starting with ethyl (benzisoxazol-3-yl)acetate. LC/MS:calculated for C₁₇H₁₇ClN₂O 300, observed m/e 301 (M+H)⁺ (2.2 min).

REFERENCE EXAMPLE 102

4-(4-Methylphenyl)-3-phenylbutan-2-amine (Mixture of 4 Isomers)

Step A 1-Phenylacetone

To a solution of N-methyl-N-methoxyacetamide (9.9 mL, 97 mmol) in ether(300 mL) at 0° C. was added benzylmagnesium chloride (97 mL a 1Msolution in ether). The cloudy, white reaction mixture was warmed toroom temperature for 2 h and then quenched by careful addition of 1Nhydrochloric acid (100 mL). The organic phase was separated, washed withbrine, dried over MgSO₄ and concentrated. The crude material waspurified by column chromatography on silica gel eluting from 0-10%EtOAc/hexane to give the title compound. ¹H NMR (500 MHz, CDCl₃): δ 7.36(t, J=7.1 Hz, 2H), 7.30 (t, J=7.3 Hz, 1H), 7.24 (d, J=7.3 Hz, 2H), 3.72(s, 2H), 2.18 (s, 3H). LC-MS: m/e 135 (M+H)⁺ (1.95 min).

Step B 4-(4-Methylphenyl)-3-phenylbutan-2-one

1-Phenylacetone (200 mg, 1.49 mmol) was mixed with powdered potassiumhydroxide (167 mg, 2.98 mmol) and tetra-n-butylammonium bromide (1 mol%, 5 mg) in a flask without solvent. This mixture was stirred at roomtemperature for 90 min. before the addition of1-(chloromethyl)-4-methylbenzene (198 μl, 1.49 mmol). The reactionmixture was then stirred overnight before diluting with water andCH₂Cl₂. The aqueous layer was separated and neutralized to pH 7 with 2Nhydrochloric acid and extracted again into CH₂Cl₂. The combined organicwashes were dried with MgSO₄ and concentrated. The crude material waspurified by column chromatography on silica gel eluting from 0-10%EtOAc/hexane to give the title compound. ¹H NMR (500 MHz, CDCl₃): δ 7.35(t, J=7.0 Hz, 2H), 7.29 (t, J=7.4 Hz, 1H), 7.23 (d, J=7.1 Hz, 2H), 7.05(d, 7.8 Hz, 2H), 6.98 (d, J=7.8 Hz, 2H), 3.94 (t, J=7.3 Hz, 1H), 3.43(dd, J=13.9, 7.5 Hz, 1H), 2.91 (dd, J=14, 7.1 Hz, 1H), 2.32 (s, 3H),2.08 (s, 3H). LC-MS: m/e 239 (M+H)⁺ (3.61 min).

Step C 4-(4-Methylphenyl)-3-phenylbutan-2-amine

To a solution of the 4-(4-methylphenyl)-3-phenylbutan-2-one (308 mg,1.29 mmol) in 7M ammonia in MeOH (5 mL) and acetic acid (3 mL) was addedsodium cyanoborohydride (130 mg, 2.06 mmol) and the reaction stirred atroom temperature overnight. The reaction was quenched by pouring into 2Msodium carbonate solution and extracted into EtOAc. The aqueous layerwas salted and re-extracted. The combined organic extracts were driedover MgSO₄ and concentrated to give the title compound as a mixture of 4isomers which was used without further purification. LC-MS: m/e 240(M+H)⁺ (2.22 min).

REFERENCE EXAMPLE 103

4-(4-Methoxyphenyl)-3-phenylbutan-2-amine

Prepared using the procedures described in Example 102, Steps A throughC using 1-(chloromethyl)-4-methoxybenzene as the alkylating agent inStep B. LC-MS: m/e 256 (M+H)⁺ (1.90 and 2.03 min).

REFERENCE EXAMPLE 104

3-[2-Amino-1-(4-fluorobenzyl)propyl]benzonitrile

Prepared using the procedures described in Example 79 using3-(2-oxopropyl)benzonitrile and 1-(chloromethyl)-4-fluorobenzene as thereactants in Step B. LC-MS: m/e 269 (M+H)⁺ (2.87 min).

REFERENCE EXAMPLE 105

N-[2-Phenyl-3-(4-fluorophenyl)-1-methylpropyl]amine hydrochloride(Diastereomer α)

The title compound was obtained by the method described in ReferenceExample 26, substituting 4-fluorobenzyl bromide for isobutyl iodide.LC-MS, R_(t)=2.2 min, m/e=244.

REFERENCE EXAMPLE 106

2-(2,3-Dihydro-1-H-indol-1-yl)-1,4-dimethylpentylamine

Step A Ethyl (2-(2,3-dihydro-1H-indol-1-yl)-4-methylpentanoate

A solution of 0.53 g (3.3 mmol) of ethyl (S)-2-hydroxyisocaproate in 8mL dry CH₂Cl₂was cooled in a −78° C. bath and 0.73 mL (4.34 mmol) oftriflic anhydride and 0.6 mL (5.36 mmol) of 2,6 lutidine were added.After 15 min 2 mL (11.5 mmol) of diisopropylethylamine was added andstirred for 10 min. To this solution 0.36 mL (3.21 mmol) of2,3-dihydroindoline was added and stirred overnight as it slowly warmedto room temperature. The reaction was quenched with saturated NaHCO₃solution and extracted with ether. The combined organic layer was washedwith water, brine, dried and concentrated. The residue was purified on aflash column using a gradient of 5-10% EtOAc/hexane to isolate the titlecompound. ¹H NMR: (500 MHz, CDCl₃): δ 0.99 (d, 3H), 1.03 (d, 3H), 1.22(t, 3H), 1.81 (m, 3H), 3.04 (m, 2H), 3.57 (m, 1H), 3.66 (m, 1H), 4.14(q, 2H), 4.24 (t, 1H), 6.4-7.1 (m, 4H).

Step B 3-(2,3-Dihydro-1H-indol-1-yl)-5-methylhexan-2-one

To a solution of 0.54 g (2.07 mmol) of ethyl(2-(2,3-dihydro-1H-indol-1-yl)-4-methylpentanoate in 10 mL CH₂Cl₂, 1.98g (10 mmol) of N,O-dimethylhydroxylamine hydrochloride and 1.4 mLtriethylamine were added. The mixture was cooled in an ice bath and 10mL (10 mmol) 1 M diethylaluminium chloride in toluene was added. Thereaction was stirred overnight as it warmed to room temperature thencarefully quenched by pouring into 1.2 N HCl. The solution was extractedwith CH₂Cl₂. The organic layer was washed with brine, dried andconcentrated leaving amide which was used without purification. Thisamide was dissolved in 5 mL THF and 2.5 mL (3.5 mmol) of 1.4 Mmethylmagnesium bromide was added. After 1 h, the solution was quenchedwith 1.2 N HCl and extraced with EtOAc. The EtOAc layer was washed withbrine, dried and concentrated. The residue was chromatographed using agradient of 5-10% EtOAc-hexane to isolate the title compound. ¹H NMR:(500 MHz, CDCl₃): δ 0.96 (d, 3H), 0.99 (d, 3H), 1.7 (m, 3H), 2.17 (s,3H), 3.06 (m, 2H), 3.04 (q, 1H), 3.52 (m, 1H), 4.11 (m, 1H) 6.4-7.1 (m,4H).

Step C 2-(2,3-Dihydro-1-H-indol-1-yl)-1,4-dimethylpentylamine

To a solution of 0.185 g (0.8 mmol) of3-(2,3-dihydro-1H-indol-1-yl)-5-methylhexan-2-one in 2 mL ethanol, 0.135g O-methylhydroxylamine hydrochloride and 0.13 mL (1.6 mmol) of pyridinewere added. After stirring for 2 h, the solution was concentrated andthe residue was partitioned between water and EtOAc. The organic layerwas washed with brine, dried and concentrated to give 0.2 gO-methyloxime as a mixture of isomers. This mixture was dissolved in 2mL THF and 1.5 mL 1 M BH₃ in THF was added. After gas evolution ceased,the reaction was heated in a 50° C. bath. After 2 h another 1.5 mL 1 MBH₃ in THF was added and heating was continued overnight. The reactionmixture was cooled and quenched with MeOH and concentrated. The residuewas dissolved in 6 mL CH₂Cl₂ and 2 mL 1 N NaOH was added. After stirringfor 15 min the layers were separated and the aqueous layer was extractedwith CH₂Cl₂. The combined organic layer was washed with water, brinedried and concentrated to isolate title compound as a mixture ofdiastereomers which was used without purification. LC-MS, R_(t)=2.24min, m/e=233.

The following amines were synthesized by the method of Reference Example106.

REFERENCE EXAMPLE 107

3-Cyclobutyl-2-(3,4-dihydroquinoline-1(2H)-yl)-1-methylpropylamine

LC-MS, R_(t)=2.8 min, m/e=259.

REFERENCE EXAMPLE 108

2-(3,4-Dihydroquinoline-1(2H)-yl)-1,4-dimethylpentylamine

LC-MS, R_(t)=2.74 min, m/e=248.

REFERENCE EXAMPLE 109

2-(1H-1,2,3-Benzotriazol-1-yl)-3-(4-chlorophenyl)-1-methylpropylamine

Step A 2-(1H-1,2,3-Benzotriazol-1-yl)-N-methoxy-N-methylacetamide

A mixture of 1.77 g (10 mmol) of 2-(1H-1,2,3-benzotriazol-1-yl)aceticacid, 1.07 g (11 mmoles) of N,O-dimethylhydroxylamine hydrochloride, 5.8g (11 mmol) of PyBOP, and 3.4 mL (24.2 mmol) of diisopropylethylamine in50 mL CH₂Cl₂ was stirred overnight at RT. This mixture was partitionedbetween EtOAc and water. The organic layer was washed with brine anddried over anhydrous MgSO4. Solvent removal afforded a crude productwhich was purified on silica gel using 60% EtOAC in hexane as solvent togive 2.01 g the desired amide as a solid. ¹H NMR: (CDCl₃): δ 3.26 (s,3H), 3.84 (s, 3H), 5.63 (s, 2H), 7.35-8.2 (m, 4H).

Step B2-(1H-1,2,3-Benzotriazol-1-yl)-3-(4-chlorophenyl)-N-methoxy-N-methyl-propanamide.

To a solution of 2.0 g (9 mmol) of2-(1H-1,2,3-benzotriazol-1-yl)-N-methoxy-N-methylacetamide in 15 mLanhydrous THF at −78° C., 10 mL (10 mmol) of 1M lithiumbis(trimethylsilyl)amide was added dropwise. After stirring for 25 min,a solution of 2.06 g (10 mmol) of 4-chlorobenzyl bromide in 2 mLanhydrous THF was added. The resulting reaction mixture was allowed towarm to RT and stirred for 6 h. This reaction was quenched, diluted with75 mL EtOAc and washed 3 times with 10 mL each of brine, After dryingthe organic phase solvent removal afforded a crude product which waspurified on silica gel using 40% EtOAc in hexane as solvent to affordthe desired product as a solid. ¹H NMR: (CDCl₃): δ 3.2 (s, 3H), 3.34 (s,3H), 3.52 (m, 1H), 3.7 (m, 1H), 6.32 (t, 1H), 6.9-8.2 (m, 8H).

Step C 2-(1H-1,2,3-Benzotriazol-1-yl)-3-(4-chlorophenyl)-butan-2-one.

To a solution of 1.73 g (5 mmol) of2-(1H-1,2,3-benzotriazol-1-yl)-3-(4-chlorophenyl)-N-methoxy-N-methyl-propanamidein 10 mL anhydrous THF at 0 ° C., 4 mL (10 mmol) of 2.5M methylmagnesium bromide in ether was added. The reaction mixture was stirredfor 4 h as it warmed to RT. The reaction was quenched by adding 10 mL 1NHCl and the resulting mixture was partitioned between EtOAc and water.The organic phase was washed with brine and dried over anhydrous MgSO₄.Solvent removal gave a crude ketone, which was purified on silica gelusing 40% EtOAc in hexane to provide the desired ketone.

Step D 2-(1H-1,2,3-Benzotriazol-1-yl)-3-(4-chlorophenyl)-1-methylpropylamine

To a solution of 1.18 g (4 mmol) of2-(1H-1,2,3-benzotriazol-1-yl)-3-(4-chlorophenyl)-butan-2-one in 8.5 mL(60 mmol) of 7N ammonia in MeOH at 0° C., 4 mL (964 mmol) of glacialacetic acid was added followed by 410 mg (6.5 mmol) of sodiumcyanoborohydride. The reaction mixture was allowed to warm to RT andstirred overnight. The reaction was partitioned between EtOAc andsaturated NaHCO₃ solution. The organic phase was dried over anhydrousMgSO₄. The solvent was removed in vacuo and the residue was purified onsilica gel using a mixture of 5% 2N methanolic ammonia solution and 95%CH₂Cl₂ to give the desired amine as a mixture of diastereomers. LC-MS,R_(t)=2.0 min, m/e=301.

REFERENCE EXAMPLE 110

3-(4-Chlorophenyl)-2-(thiophene-3-yl)-1-methylpropylamine

The title amine was prepared by the method described in ReferenceExample 109, substituting thiophene-3-acetic acid for2-(1H-1,2,3-benzotriazol-1-yl)acetic acid in Step A. LC-MS, R_(t)=2.19min, m/e=266.

REFERENCE EXAMPLE 111

3-(4-Chlorophenyl)-2-(thiophene-2-yl)-1-methylpropylamine

Step A 3-(4-Chlorophenyl)-2-(thiophen-2-yl)-butan-2-one.

The title compound was obtained from 2-thiopheneacetic acid according tothe procedure described in Reference Example 26, Steps A-C.

Step B 3-(4-Chlorophenyl)-2-(thiophene-2-yl)-1-methylpropylamine

This amine was synthesized by the method of Reference Example 109, StepD. LC-MS, R_(t)=2.18 min, m/e=266.

REFERENCE EXAMPLE 112

3-(4-Chlorophenyl)-1-methyl-2-(1-methyl-1H-indol-3-yl)propylamine

The title compound was prepared according to the method described inReference Example 111. LC-MS: R_(t)=2.5 min, m/e=313.

REFERENCE EXAMPLE 113

3-(4-Chlorophenyl)-1-methyl-2-(1H-indazol-1-yl)propylamine

Step A 3-(4-Chlorophenyl)-2-(1H-indazol-1-yl)-butan-2-one.

The title compound was obtained from indazol-1-yl-acetic acid byfollowing the procedure of Reference Example 10, Steps A-D.

Step B 3-(4-Chlorophenyl)-1-methyl-2-(1H-indazol-1-yl)propylamine.

The title amine was prepared according to the procedure of ReferenceExample 106, Step C. LC-MS: Rt=2.24 min, m/e=300.

REFERENCE EXAMPLE 114

3-(4-Chlorophenyl)-1-methyl-2-(1-methyl-1H-indol-4-yl)propylamine

Step A 4-Chloro-1-methylindole

In a 100 mL flask, 0.3 g (7.5 mmol) sodium hydride was washed twice withdry hexane. The solid was suspended in 15 mL dry THF and 1 g (6.6 mmol)4-chloroindole was drop wise added. After 15 min, 0.5 mL (7.9 mmol)methyl iodide was added and the solution was stirred overnight. Thereaction was quenched with 1.2 N HCl and partitioned between ether andwater. The organic layer was washed with brine, dried and concentratedkeeping the bath temperature below 30° C. The residue was purified on aflash column using a gradient of 5-10% EtOAc/hexane to isolate thedesired product. ¹H NMR: (500 MHz, CDCl₃): δ 3.84 (s, 3H), 6.63 (d, 1H),7-7.3 (m, 4H).

Step B 1-(1-Methyl-1H-indol-4-yl)acetone

To a solution of 0.852 g (5.14 mmol) of 4-chloro-1-methylindole in 15 mLdry toluene, 0.85 mL (7.73 mmol) isopropenyl acetate and 2.3 mL (8 mmol)tributyltin methoxide were added. The solution was heated to 100° C.After 15 min 0.24 g (0.61 mmol)2-dicyclohexylphospino-2′-(N,N-dimethylamino)biphenyl and 0.14 g (0.153mmol) tris(dibenzylidineacetone)dipalladium were added and heating wascontinued. After 2 h the solution was cooled, filtered through a pad ofCELITE diatomaceous earth and the filtrate was concentrated to ca. 5 mL.This solution was purified on a silica column using a gradient of 5-20%EtOAc/hexane to obtain the title compound. ¹H NMR: (500 MHz, CDCl₃): δ2.14 (s, 3H), 3.84 (s, 3H), 3.97 (s, 2H), 6.51 (d, 1H), 7-7.3 (m, 4H).

Step C 4-(4-Chlorophenyl)-3-(1-methyl-1H-indol-4-yl)-butan-2-one

To a suspension of 135 mg (3.38 mmol) of sodium hydride in 8 mL dry THF,a solution of 605 mg (3.23 mmol) 1-(1-methyl-1H-indol-4-yl)acetone in 2mL THF was added. The mixture was stirred for 45 min during which timethe sodium hydride dissolved and a yellow orange solution resulted. Thereaction was cooled in ice bath and 660 mg (3.24 mmol) 4-chlorobenzylbromide in 1 mL THF was added. The cold bath was removed and thesolution was stirred for 1.5 h. The reaction was quenched with 1.2 N HCland extracted with EtOAc. The organic layer was washed with brine, driedand concentrated. The residue was chromatographed using a gradient of10-20% EtOAc/hexane to isolate the desired product. ¹H NMR: (500 MHz,CDCl₃): δ 2.03 (s, 3H), 3.07 (m, 1H), 3.58 (m, 1H), 3.84 (s, 3H), 4.23(t, 1H), 6.52 (d, 1H), 6.9-7.3 (m, 8H).

Step D 3-(4-Chlorophenyl)-1-methyl-2-(1-methyl-1H-indol-4-yl)propylamine

The title compound was prepared from4-(4-chlorophenyl)-3-(1-methyl-1H-indol-4-yl)-butan-2-one by followingthe procedure of Reference Example 106, Step C. LC-MS, Rt=2.4 min,m/e=313.

REFERENCE EXAMPLE 115

3-(4-Chlorophenyl)-1-methyl-2-(pyridazin-3-yl)propylamine

Step A 4-(4-Chlorophenyl)-3-(pyridazin-3-yl)-butan-2-one

This compound was synthesized from 3-iodopyridazine by the procedure ofReference Example 114, Steps B-C.

Step BN-2,4-Dimethoxybenzyl-N(3-(4-chlorophenyl)-1-methyl-2-(pyridazin-3-yl)propyl)amine

A solution of 300 mg (1.15 mmol)4-(4-chlorophenyl)-3-(pyridazin-3-yl)-butan-2-one in 4 mL dichloroethanewas treated with 234 mg (1.15 mmol) 2,4-dimethoxybenzyl aminehydrochloride, 0.16 mL (1.15 mmol) triethylamine and 488 mg (2.3 mmol)sodium triacetoxyborohydride. After stirring the reaction overnight, itwas partitioned between water and CH₂Cl₂. The organic layer was washedwith brine, dried and concentrated and the residue was purified on aflash column using 3% MeOH—CH₂Cl₂to isolate the desired amine.

Step C 3-(4-Chlorophenyl)-1-methyl-2-(pyridazin-3-yl)propylamine

A solution of 300 mgN-2,4-dimethoxybenzyl-N(3-(4-chlorophenyl)-1-methyl-2-(pyridazin-3-yl)propyl)aminein 5 mL trifluoroacetic acid was heated in a 70° C. bath over nightfollowed by 6 h in a 100° C. bath. The reaction was cooled, concentratedand the residue was diluted with EtOAc. This solution was quenched (topH 10) with 1N NaOH and the layers were separated. The organic layer waswashed with brine, dried and concentrated. The residue was purified on aprep TLC using 10% MeOH/CH₂Cl₂ with 1% NH₄OH to isolate the titlecompound (mixture of diastereomers), starting material was alsorecovered. LC-MS, Rt=1.63 min, m/e=262.

REFERENCE EXAMPLE 116

3-(4-Chlorophenyl)-1-methyl-2-(pyrimidin-5-yl)propylamine

Step A 4-(4-Chlorophenyl)-3-(pyrimidin-5-yl)-butan-2-one

The title compound was obtained from 5-bromopyrimidine following themethod of Reference Example 114, Steps B-C except that2-(di-t-butylphosphino)biphenyl was used in place ofdicyclohexylphospino-2′-(N,N-dimethylamino)biphenyl in Step B.

Step B 3-(4-Chlorophenyl)-1-methyl-2-(pyrimidin-5-yl)propylamine

The title compound was prepared by the procedure described in ReferenceExample 10, Steps E-I. LC-MS, Rt=1.57 min, m/e=262.

REFERENCE EXAMPLE 117

2-(3-Cyanophenyl)-3-cyclobutyl-1-methylpropylamine

Step A 3-(3-Cyanophenyl)acetone

The title compound was prepared from 3-bromobenzonitrile and isopropenylacetate by the procedure of Reference Example 114, Step B.

Step B 3-(3-Cyanophenyl)-4-cyclobutyl-butan-2-one

To a solution of 1.45 g (9.07 mmol) of 1-(3-cyanophenyl)acetone in 18 mLacetonitrile, 1.1 mL (9.5 mmol) cyclobutyl bromide and 5.91 g (18.1mmol) cesium carbonate were added. After heating the solution in a 60°C. bath overnight, it was cooled and filtered. The filtrate waspartitioned between water and EtOAc and the aqueous layer was extractedwith EtOAc. The combined organic layer was washed with brine, dried andconcentrated. The residue was purified on a flash column using agradient of 5-10% EtOAc/hexane to isolate the title compound. ¹H NMR:(500 MHz, CDCl₃): δ 1.5-2.2 (m, 9H), 2.13 (s, 3H), 3.64 (m, 1H), 7.4-7.7(m, 4H)

Step C 2-(3-Cyanophenyl)-3-cyclobutyl-1-methylpropylamine

This amine was prepared by following the method of Reference Example 10,Steps E-I. LC-MS, Rt=2.48 min, m/e=229.

The compounds of Reference Examples 118-120 were obtained by proceduresdescribed in Reference Example 117.

REFERENCE EXAMPLE 118

2-(3-Cyanophenyl)-3-cyclopropyl-1-methylpropylamine

LC-MS, Rt=1.8 min, m/e=215.

REFERENCE EXAMPLE 119

2-(3-Cyanophenyl)-3-cyclopentyl-1-methylpropylamine

LC-MS, Rt=2.7 min, m/e=243.

REFERENCE EXAMPLE 120

2-(3-Cyanophenyl)-3-cyclohexyl-1-methylpropylamine

LC-MS, Rt=2.8 min, m/e=257.

REFERENCE EXAMPLE 121

2-(3-Cyanophenyl)-3-(1-tert-butyloxycarbonyl-piperidin-4-yl)-1-methylpropylamine

Step A3-(3-Cyanophenyl)-4-(1-tert-butyloxycarbonyl-piperidin-4-yl)-butan-2-one

The title compound was synthesized by the method of Reference Example117, Steps A-B.

Step B2-(3-Cyanophenyl)-3-(1-tert-butyloxycarbonyl-piperidin-4-yl)-1-methylpropylamine

The title amine was obtained by the method of Reference Example 10,steps E-G except that di-tert-butyl dicarbonate was not added in Step G.LC-MS, Rt=2.72 min, m/e=258 (M-99).

REFERENCE EXAMPLE 121

2-Methyl-2-(5-methylsulfonyl-2-pyridyloxy)propionic Acid

Step A Ethyl 2-(5-Methylsulfonyl-2-pyridyloxy)propionate

A mixture of ethyl 2-hydroxyisobutyrate (0.41 mL, 3.0 mmol),2,5-bis(methylsulfonyl)pyridine (J. Heterocycl. Chem. 1985, 22, 1583)(0.70 g, 3.0 mmol) and sodium hydride (60% dispersion in mineral oil,0.14 g, 3.6 mmol) in 30 mL of anhydrous DMF was heated at 80° C.overnight. The reaction mixture was cooled to room temperature, and waspartitioned between saturated aqueous ammonium chloride (200 mL) andether (200 mL). The organic layer was separated and was washed withwater and brine, dried over anhydrous sodium sulfate, filtered andconcentrated to dryness, and the residue was purified by flash columnchromatography on silica gel eluting with 0 to 80% ethyl acetate inhexane to give the title compound as a 1:1 mixture with2-ethoxy-5-methylsulfonylpyridine. LC-MS: m/e 288 (M+H)⁺ (0.70 min).

Step B 2-Methyl-2-(5-methylsulfonyl-2-pyridyloxy)propionic Acid

To a solution of ethyl2-methyl-2-(5-methylsulfonyl-2-pyridyloxy)propionate (Step A, 0.45 g,1.6 mol) in 5 mL MeOH, 10 mL THF and 10 mL water was added sodiumhydroxide (0.19 g, 4.7 mmol). After stirring at room temperature for 3days, the reaction mixture was partially concentrated, and was added 2 Mhydrochloric acid to pH>2. The resulting mixture was extracted withEtOAc (2×20 mL), and the combined extracts were dried over anhydroussodium sulfate filtered, and concentrated to dryness to afford the titlecompound. ¹H NMR (500 MHz, CD₃OD): δ 8.60 (d, 1H), 8.16 (dd, 1H), 7.17(d, 1H), 3.15 (s, 3H), 1.71 (s, 6H).

REFERENCE EXAMPLE 122

N-[3-(4-Chlorophenyl)-2-(3-methylthiophenyl)-1-methylpropyl]amineHydrochloride (Diastereomer α)

The title compound was prepared following the same procedure asdescribed in Example 69 substituting 3,5-dibromopyridine with3-bomothioanisole at Step A. LC-MS: m/e 306 (M+H)⁺ (2.68 min).

EXAMPLE 1

Automated Synthesis of a One Dimensional Amide Library

The following synthesis of a 1-dimensional, single, pure compoundlibrary was performed on a MYRIAD CORE System. All reaction vessels weredried under a stream of nitrogen at 120° C. for 12 h prior to use. Allsolvents were dried over sieves for at least 12 h prior to use. Anappropriate stock solution ofN-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride (alphaisomer) was prepared immediately prior to use in pyridine with 0.05equivalents (relative toN-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hyrdochloride (alphaisomer)) of dimethylaminopyridine added; the diverse carboxylic acidsavailable from commercial sources were dissolved immediately prior touse in DMSO. The relative amounts of reactants and coupling reagents arelisted in Table 1. Compounds of the present invention that were preparedby this method of automated synthesis are listed in Table 2.

TABLE 1 Amount per reaction Concen- Substance vessel MW tration mmolsEquivs. Acid in DMSO   1 mL N/A 0.2 M 0.2 1.67 EDC/HOBt Cocktail 0.8 mLEDC: 0.25 M 0.2 each 1.67 in Deuterated 191.71 each each ChloroformHOBt: 135.13 Amine in Pyridine 0.6 mL 294.227 0.2 M 0.12 1.0 withcatalytic dimethylaminopyridine (˜0.05 eq.)Procedure

To vessel one of a total of 192 dry, 10 mL fritted MYRIAD reactionvessels under nitrogen was added the appropriate diverse acid subunit(1.0 mL, 0.2 mmoles, 0.2 M in DMSO); this was repeated for the remaining191 reactions until the diversity acids had been enumerated to all 192reaction vessels. To each of 192 reaction vessels under nitrogen wasthen added the EDC/HOBt cocktail (0.8 mL, 0.2 mmoles, 0.25 M each indeuterated chloroform). Finally, to each of the 192 reaction vessels wasadded N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride(alpha isomer) (0.6 mL, 0.12 mmoles, 0.2M in pyridine). The reactionswere then aged for 4 h at room temperature (20-25° C.) followed by 16 hat 65° C. with nitrogen sparging agitation (1 s pulse of nitrogen every30 minutes). The crude reactions were analyzed by HPLC-MS Method 1.

Column: MetaChem Polaris C-18A, 30 mm × 4.6 mm, 5.0 μm Eluent A: 0.1%TFA in Water Eluent B: 0.1% TFA in Acetonitrile Gradient: 5% B to 95% Bin 3.3 minutes, ramp back to 5% B in 0.3 min Flow: 2.5 mL/min. ColumnTemp.: 50° C. Injection amount: 5 uL of undiluted crude reactionmixture. Detection: UV at 220 and 254 nm. MS: API-ES ionization mode,mass scan range (100-700) ELSD: Light Scattering Detector

All 192 crude reactions were purified by preparative HPLC using UV baseddetection (Preparative method 2). The collected fractions were thenanalyzed for purity by LC-MS (Analytical method 3); fractions found tobe greater than 90% purity were pooled into tared 40 mL EPA vials andlyophilized.

Preparative LC Method 2:

Column: MetaChem Polaris C-18A, 100 mm × 21.2 mm, 10 μm Eluent A: 0.1%TFA in Water Eluent B: 0.1% TFA in Acetonitrile Pre-injectEquilibration: 1.0 min Post-Inject Hold: 0.0 min Gradient: 10% B to 100%B in 6.0 minutes, hold at 100% B for an additional 2.0 minutes, rampback from 100% B to 10% B in 1.5 minutes. Flow: 25 mL/min. Column Temp.:ambient Injection amount: 1.5 mL undiluted crude reaction mixture.Detection: UV at 220 and 254 nm.Analytical LC Method 3:

Column: MetaChem Polaris C-18A, 30 mm × 2.0 mm, 3.0 μm Eluent A: 0.1%TFA in Water Eluent B: 0.1% TFA in Acetonitrile Gradient: 5% B to 95% Bin 2.0 minutes, ramp back to 5% B in 0.1 min Flow: 1.75 mL/min. ColumnTemp.: 60° C. Injection amount: 5 uL of undiluted fraction. Detection:UV at 220 and 254 nm. MS: API-ES ionization mode, mass scan range(100-700) ELSD: Light Scattering DetectorLyophilization Parameters

Initial Freeze Setpoint: 1 h at −70° C.

Drying Phase Condenser Setpoint: −50° C.

Drying Phase Table:

Shelf Temperature (C.) Duration (minutes) Vacuum Setpoint (mTorr) −60°240 25 −40° 240 25    5° 480 25   20° 1000 25

TABLE 2 Compounds prepared by automated synthesis (the followingcompounds are racemic, and the structures imply relative stereochemistryonly). HPLC- retention mass Ex. time spectrum No. Name Structure (min)m/e 1. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-2-(py-razol-1-yl)acetamide, trifluoroacetic acid salt

1.33 402.2 2. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(1,2,4-tri- azol-1-yl)acetamide, trifluoroacetic acid salt

1.190 403.05 3. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(benzo- thiazole-2-thio) acetamide, trifluoroacetic acidsalt

1.54 501.2 4. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-2-(benzo-xazole-2-thio) acetamide, trifluoroacetic acid salt

1.50 485.2 5. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-2-(benzo-xazolin-2-on-3-yl) acetamide

1.365 469.05 6. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(4-meth- yl-2H-phthalazin-1-on-2-yl) acetamide

1.353 494.10 7. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(2H-phthala- zin-1-on-4-yl)propanamide

1.34 494.3 8. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-2-(3,5-di-methyl-1,2,4-triazol-1-yl) acetamide, trifluoroacetic acid salt

1.2 431.3 9. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-2-(2-meth-yl-thiazol-4-yl)acetamide, trifluoroacetic acid salt

1.33 433.2 10. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(1-(4-phenyl-py- rrolidin-2-on-1-yl))acetamide

1.42 495.3 11. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(3,5-di- methyl-py- razol-1-yl)acetamide, trifluoroaceticacid salt

1.285 430.2 12. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(3-meth- yl-pyrazol-1-yl)acetamide, trifluoroacetic acidsalt

1.33 430.3 13. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-2-(iso-indolin-1-on-3-yl)acetamide

1.276 467.10 14. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(3,5-di- methyl-iso- xazol-4-yl)acetamide, trifluoroaceticacid salt

1.316 431.1 15. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-3-(3,5-di- methyl-py- razol-1-yl)propanamide, trifluoroaceticacid salt

1.29 444.3 16. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(3-meth- yl-pyrazol-1-yl)acetamide, trifluoroacetic acidsalt

1.303 416.10 17. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(4-(imi- dazolidin-2-on-1-yl)phenyl)a- cetamide

1.258 496.2 18. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-pro-pyl]-2-(5-methyl-1,2,4-tri- azol-3-yl)acetamide, trifluoroacetic acidsalt

1.17 417.2 19. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-5-(2-meth- yl)phenyl-5-oxo-pentanamide

1.436 482.1 20. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-3-(benzo- thiazol-2-yl)propanamide, trifluoroacetic acid salt

1.46 483.2 21. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-3-(aza-bi- cyclo[2.2.1]hep- tan-2-yl)propanamide,trifluoroacetic acid salt

1.154 445.2 22. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(5-meth- oxy-2-oxo-2,3-di- hydro-1H-indol-3-yl)aceta- mide

1.270 497.1 23. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(benzo- triazol-2-yl)acetamide, trifluoroacetic acid salt

1.44 453.2 24. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(4-meth- yl-thiazol-2-yl-thio)acetamide, trifluoroaceticacid salt

1.404 465.0 25. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(4,4-di- phenyl)butanamide

1.543 516.15 26. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-3-(1,2,4-tri- azol-1-yl)propanamide, trifluoroacetic acidsalt

1.180 417.15 27. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-2-(imi-dazo[2,1-b][1,3]thia- zol-6-yl)acetamide, trifluoroacetic acid salt

1.16 458.1 28. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-3-(3,5-di- chlorophenyl)propanamide

1.533 496.0 29. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-4-(3,5-di- chlorophenyl)butanamide

1.575 510.0 30. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-3-(t-bu-toxy)propanamide

1.397 422.1 31. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-4-(2,3-di- hydro-indol-1-yl)butanamide

1.195 481.2 32. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-3-(1-meth- yl-pyrazol-5-yl)propanamide, trifluoroacetic acidsalt

1.230 430.2 33. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-3-(4-t-butoxy- phenyl)-pro- panamide

1.498 498.1 34. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-3-(3,5-di- methylphenyl)propanamide

1.499 454.2 35. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(5-methyl- -pyrazol-1-yl)acetamide, trifluoroacetic acidsalt

1.294 416.1 36. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(4-meth- yl-1,2,4-tria- zol-3-yl-thio)acetamide,trifluoroacetic acid salt

1.180 449.1 37. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(2,3,4,5-tetra- hydro-1,4-benzoxa- zepin-4-yl)acetamide,trifluoroacetic acid salt

1.190 483.1 38. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-6-(t-butyl- oxycarbonyl- amino)hexanamide

1.415 407.1 (-BOC) 39. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(5,6-dihydro-imi- dazo[2,1-b]thia- zol-3-yl)acetamide,trifluoroacetic acid salt

1.134 460.0 40. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(morpho- lin-4-yl)-2-(3-py- ridyl)acetamide,trifluoroacetic acid salt

1.14 498.2 41. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-4-(amino-sulfonyl)-butanamide

1.198 443.1 42. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(4-phenyl-pipera- zin-1-yl)acetamide, trifluoroacetic acidsalt

1.210 496.2 43. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-trans-cinnamamide

1.438 424.15 44. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-pro-pyl]-9-phenyl-9-oxo-nona- namide

1.519 524.3 45. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-phenyl-butana- mide

1.483 440.1 46. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-2-cyclo-propyl-aceta- mide

1.350 376 47. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-2-(1-naph-thyl)-acetamide

0.918 459.3 48. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(5-meth- oxy-1-inda- non-3-yl)-acetamide

1.35 496.2 49. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-phenoxy-aceta- mide

1.430 428.1 50. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-3-(4-hy-droxyphenyl)-propanamide

1.248 442.0 51. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-hexanamide

1.436 392.1 52. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-2-cyclo-pentyl-acetamide

1.49 404.2 53. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-2-eth-oxy-acetamide

1.346 380.1 54. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-3-meth-yl-butanamide

1.380 378.1 55. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-3-(1-t-bu- toxycarbonyl-pipe- ridin-4-yl)-propana- mide

1.52 433.3 (-BOC) 56. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-2-(3-chloro- phenyl)-acetamide

0.879 445.2 57. N-[2,3-bis(4-chloro- phenyl)-1-meth-yl-propyl]-3-(4-chloro- phenyl)-propanamide

1.462 462.1 58. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-2-hy-droxy-2-phenyl-aceta- mide

1.346 428.1 59. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-2-hy-droxy-2-(4-meth- oxy-phenyl)-acetamide

1.335 458.1 60. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-2-meth-oxy-2-phenyl-acetamide

1.48 442.0 61. N-[2,3-bis(4-chloro- phenyl)-1-meth- yl-propyl]-2-hy-droxy-2,2-di- phenyl-acetamide

1.500 504.11

EXAMPLES 62 and 63

N-[2,3-Bis(4-Chlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide(Diastereomers α and β)

To a solution of 2-(4-chlorophenyloxy)-2-methylpropionic acid (Aldrich,0.22 g, 1.0 mmol) in CH₂Cl₂ (2 mL) at 0° C. was added a drop of DMF andoxalyl chloride (0.27 mL, 3.0 mmol). After stirring at room temperaturefor 1 h, the reaction mixture was concentrated on a rotary evaporatorand dried under vacuum, and the resulting crude acyl chloride was usedwithout further purification. Thus, the crude acyl chloride wasdissolved in 1 mL CH₂Cl₂ and was added to a suspension of2-amino-3,4-bis(4-chlorophenyl) butane hydrochloride salt (ReferenceExample 1) (diastereomer α contaminated with some diastereomer β, 0.20g, 0.60 mmol) and N-methylmorpholine (0.27 mL, 2.4 mmol) in 4 mL CH₂Cl₂.After stirring at room temperature for 6 h, the reaction mixture wasloaded onto a silica gel column, which was eluted with 10% EtOAc to givea pure faster eluting isomer (diastereomer α) and a slower elutingisomer (diastereomer β).

Diastereomer α: ¹H NMR (500 MHz, CD₃OD): δ 7.24 (d, 2H), 7.20 (d, 2H),7.05 (d, 2H), 7.01 (d, 2H), 6.94 (d, 2H), 6.76 (d, 2H), 4.25 (m, 1H),3.03 (dd, 1H), 2.88 (ddd, 1H), 2.67 (dd, 1H), 1.59 (s, 3H), 1.53 (s,3H), 0.88 (d, 3H). LC-MS: m/e 490 (M+H)⁺ (4.7 min).

Diastereomer β: ¹H NMR (500 MHz, CD₃OD): δ 7.16 (d, 2H), 7.14 (d, 2H),7.09 (d, 2H), 6.99 (d, 2H), 6.88 (d, 2H), 6.64 (d, 2H), 4.33 (m, 1H),3.12 (dd, 1H), 3.03 (ddd, 1H), 2.74 (dd, 1H), 1.36 (s, 3H), 1.30 (d,3H), 1.30 (s, 3H). LC-MS: m/e 490(M+H)⁺ (4.7 min).

Examples 64-148 (Table 3) were prepared following the proceduresdescribed in Examples 62 and 63 substituting2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt with theappropriate amines from the Reference Examples and2-(4-chlorophenyloxy)-2-methylpropionic acid with the appropriate acidsfrom the Reference Examples. In some cases, commercial acids or acylchlorides were employed, and N-diisopropyl-ethylamine may be used inplace of N-methylmorpholine with similar results. The diastereomerdesignations (α or β) correspond to designations of the starting amines.

TABLE 3 Compounds prepared according to the methods described inExamples 62-63. HPLC- retention mass Diastereomer Ex. time spectrum αand/ No. Name Structure (min) m/e or β 64. N-[2,3-Bis(4-chloro-phenyl)-1-methyl- propyl]-2-(4-cyclo- hexyloxy)-2-methyl-propanamide^(a)

4.8 462 α 65. N-[2,3-Bis(4-chloro- phenyl)-1-methyl- propyl]-2-(4-cyclo-hexyloxy)-2-methyl- propanamide^(a)

4.9 462 β 66. N-[2,3-Bis(4-chloro- phenyl)-1-methyl-propyl]-2-(2-fluoro- phenyl- oxy)-2-methyl- propanamide

4.5 474 α 67. N-[2,3-Bis(4-chloro- phenyl)-1-methyl-propyl]-2-(3-fluoro- phenyl- oxy)-2-methyl- propanamide

4.5 474 α 68. N-[2,3-Bis(4-chloro- phenyl)-1-methyl- propyl]-2-(3,4-di-fluoro- phenyl- oxy)-2-methyl- propanamide

4.5 492 α 69. N-[2,3-Bis(4-chloro- phenyl)-1-methyl-propyl]-2-(3-chloro- phenyl- oxy)-2-methyl- propanamide

4.7 490 α 70. N-[2,3-Bis(4-chloro- phenyl)-1-methyl-propyl]-2-(2-chloro- phenyl- oxy)-2-methyl- propanamide

4.7 490 α 71. N-[2,3-Bis(4-chloro- phenyl)-1-methyl- propyl]-2-(3,5-di-fluoro- phenyloxy)-2-methyl- propanamide

4.5 492 α 72. N-[2,3-Bis(4-chloro- phenyl)-1-methyl- propyl]-2-(3-cyano-phenyloxy)-2-methyl- propanamide

4.2 481 α 73. N-[3-(4-Chloro- phenyl)-2-(2,4-di- chloro-phenyl)-1-methyl- propyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

4.9 524 α 74. N-[3-(4-Chloro- phenyl)-2-(2,4-di- chloro-phenyl)-1-methyl- propyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

4.9 524 β 75. N-[2,3-Bis(4-chloro- phenyl)-1-methyl- propyl]-2-phenyl-oxy-2-methyl- propanamide

4.5 456 α 76. N-[2,3-Bis(4-chloro- phenyl)-1-methyl-propyl]-2-(4-fluoro- phenyloxy)-2-methyl- propanamide

4.5 474 α 77. N-[2,3-Bis(4-chloro- phenyl)-1-methyl- propyl]-2,2-di-methylpropanamide

4.0 378 α 78. N-[2,3-Bis(4-chloro- phenyl)-1-methyl- propyl]-4-chloro-phenyl-carba- mate

4.8 448 α 79. N-[2,3-Bis(4-chloro- phenyl)-1-methyl-propyl]-N′-(4-chloro- phenyl)urea^(b)

4.3 447 α 80. N-[2,3-Bis(4-chloro- phenyl)-1-methyl- propyl]benzyl-carbamate

4.3 428 α 81. N-[2,3-Bis(4-chloro- phenyl)-1-methyl- propyl]-tert-butyl-carbamate^(c)

4.5 394 α 82. N-[2,3-Bis(4-chloro- phenyl)-1-methyl- propyl]-2-(3-py-ridyloxy)-2-methyl- propanamide

3.0 457 α 83. N-[2,3-Bis(4-chloro- phenyl)-1-methyl- propyl]-2-(2-py-ridylox)-2-methyl- butanamide

4.3 471 α 84. N-[2,3-Bis(4-chloro- phenyl)-1-methyl- propyl]-2-(2-py-ridyloxy)-2-methyl- propanamide

4.1 457 α 85. N-[2,3-Bis(4-chloro- phenyl)-1-methyl- propyl]-2-(4-py-ridyloxy)-2-methyl- propanamide

3.0 457 α 86. N-[3,4-Bis(4-Chloro- phenyl)-1-methyl-propyl]-2-(2-methoxy- phenyloxy)-propena- mide

4.3 470 α 87. N-[3,4-Bis(4-Chloro- phenyl)-1-methyl-propyl]-2-(2-methoxy- phenyloxy)-propena- mide

4.3 470 β 88. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-phenyl-propyl]-2-(2-fluoro- phenyloxy)-2-methyl- propanamide

4.3 440 α 89. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-phenyl-propyl]-2-(3-fluoro- phenyloxy)-2-methyl- propanamide

4.3 440 α 90. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-phenyl-propyl]-2-(3,4-di- fluoro- phenyloxy)-2-methyl- propanamide

4.3 458 α 91. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-phenyl-propyl]-2-(3-chloro- phenyloxy)-2-methyl- propanamide

4.5 456 α 92. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-phenyl-propyl]-2-(2-chloro- phenyloxy)-2-methyl- propanamide

4.4 456 α 93. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-phenyl-propyl]-2-(3,5-di- fluoro- phenyloxy)-2-methyl- propanamide

4.4 458 α 94. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-phenyl-propyl]-2-cyclo- hexyloxy-2-methyl- propanamide

4.6 428 α 95. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-phenyl-propyl]-2-(4-fluoro- phenyloxy)-2-methyl- propanamide

4.3 440 β 96. N-[3-(4-Chloro- phenyl)-2-(2-fluoro- phenyl)-1-methyl-propyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

4.4 474 α 97. N-[3-(4-Chloro- phenyl)-2-(3-fluoro- phenyl)-1-methyl-propyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

4.4 474 α 98. N-[3-(4-Chloro- phenyl)-2-(3-fluoro- phenyl)-1-methyl-propyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

4.4 474 α:β 1:10 99. N-[3-(4-Chloro- phenyl)-2-(2-fluoro-phenyl)-1-methyl- propyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

4.4 474 α:β 1:3 100. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-phenyl-propyl)]-2-meth- yl-2-phenyl- propanamide

4.2 406 α 101. N-[3-(4-Chloro- phenyl)-2-(3-fluoro- phenyl)-1-meth-ylpropyl]-2-(2-py- ridyloxy)-2-methyl- propanamide

3.9 440 α 102. N-[3-(4-Chloro- phenyl)-2-(3-fluoro- phenyl)-1-meth-ylpropyl]-2-(3,5-di- fluoro- phenyloxy)-2-methyl- propanamide

4.3 476 α 103. N-[3-(4-Chloro- phenyl)-2-(3-fluoro- phenyl)-1-meth-ylpropyl]-2-(3,5-di- fluoro- phenyloxy)-2-methyl- propanamide

4.3 476 β 104. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-phenyl-propyl]-2-(3-py- ridyloxy)-2-methyl- propanamide

2.8 423 α 105. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-phenyl-propyl]-2-(2-py- ridyloxy)-2-methyl- butanamide

4.1 437 α 106. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-phenyl-propyl]-2-(2-py- ridyloxy)-2-methyl- propanamide

3.9 423 α 107. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-phenyl-propyl]-2-(4-py- ridyloxy)-2-methyl- propanamide

2.8 423 α 108. N-[2-(4-Chloro- phenyl)-1-meth- yl-3-phenyl-propyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

4.5 456 α:β 1:1 109. N-[2-(4-Chloro- phenyl)-1-meth- yl-3-phenyl-propyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

4.5 456 β 110. N-[2-(4-Chloro- phenyl)-1-meth- yl-3-phenyl-propyl]-2-(4-fluoro- phenyloxy)-2-methyl- propanamide

4.3 440 α 111. N-[2-(4-Chloro- phenyl)-1-meth- yl-3-phenyl-propyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

4.4 456 α 112. N-[3-(4-Methoxy- carbonyl- phenyl)-1-meth- yl-2-phenyl-propyl]-2-(4-fluoro- phenyloxy)-2-methyl- propanamide

4.0 464 α 113. N-[3-(4-Methoxy- carbonyl- phenyl)-1-meth- yl-2-phenyl-propyl]-2-(4-fluoro- phenyloxy)-2-methyl- propanamide

4.0 464 β 114. N-[3-(4-Methoxy- carbonyl- phenyl)-1-meth- yl-2-phenyl-propyl]-2-(4-fluoro- phenyloxy)-2-methyl- propanamide

4.0 464 α:β 1:2 115. N-[3-(4-Methoxy- carbonyl- phenyl)-1-meth-yl-2-phenyl- propyl]-2-(4-Chloro- phenyl- oxy)-2-methyl- propanamide

4.2 480 α 116. N-[2-(2-Chloro- phenyl)-1-meth- yl-3-phenyl-propyl]-2-(4-fluoro- phenyloxy)-2-meth- ylpropanamide

4.2 440 α 117. N-[2-(2-Chloro- phenyl)-1-meth- yl-3-phenyl-propyl]-2-(4-fluoro- phenyloxy)-2-methyl- propanamide

4.2 440 β 118. N-[2-(2-Chloro- phenyl)-1-meth- yl-3-phenyl-propyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

4.2 440 α:β 2:5 119. N-[2-(2-Chloro- phenyl)-1-meth- yl-3-phenyl-propyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

4.4 456 β 120. N-[2-(4-Methoxy- phenyl)-1-meth- yl-3-phenyl-propyl]-2-(4-fluoro- phenyloxy)-2-methyl- propanamide

4.0 436 α:β 2:5 121. N-[2-(4-Methoxy- phenyl)-1-meth- yl-3-phenyl-propyl]-2-(4-chloro- phenyl- oxy)-2-methyl- propanamide

4.2 452 α:β 1:2 122. N-[2-(4-Chloro- phenyl)-3-(2,4-di-chlorophenyl)-1-meth- yl-propyl]-2-(4-chloro- phenyloxy)-2-methyl-propanamide

4.9 524 isomer 1^(d) 123. N-[2-(4-Chloro- phenyl)-3-(2,4-di-chlorophenyl)-1-meth- yl-propyl]-2-(4-chloro- phenyloxy)-2-methyl-propanamide

4.9 524 isomer 2:isomer 31:1^(e) 124. N-[2-(4-Chloro- phenyl)-3-(2,4-di-chlorophenyl)-1-meth- yl-propyl]-2,2-di- methylpropanamide

4.2 412 isomer 2^(e) 125. N-[2-(4-Chloro- phenyl)-3-(2,4-di-chlorophenyl)-1-meth- yl-propyl]-2,2-di- methylpropanamide

4.3 412 isomer 3^(e) 126. N-[2-(4-Chloro- phenyl)-3-(2,4-di-chlorophenyl)-1-meth- yl-propyl]-2,2-di- methylpropanamide

4.2/4.3 412 isomer 2:isomer 31:1^(e) 127. N-[2-(4-Chloro-phenyl)-2-(4-chlo- ro-2-fluoro- phenyl)-1-meth- yl-propyl]-2-(4-chloro-phenyloxy)-2-methyl- propanamide

4.7 508 isomer 1^(d) 128. N-[2-(4-Chloro- phenyl)-2-(4-chlo-ro-2-fluoro- phenyl)-1-meth- yl-propyl]-2-(4-chloro-phenyloxy)-2-methyl- propanamide

4.7 508 isomer 2^(e) 129. N-[2-(4-Chloro- phenyl)-2-(4-chlo-ro-2-fluoro- phenyl)-1-meth- yl-propyl]-2-(4-chloro-phenyloxy)-2-methyl- propanamide

4.7 508 isomer 3^(e) 130. N-[2-(4-Chloro- phenyl)-2-(4-chlo-ro-2-fluoro- phenyl)-1-meth- yl-propyl]-2-(4-fluoro-phenyloxy)-2-methyl- propanamide

4.6 492 isomer 2^(e) 131. N-[2-(4-Chloro- phenyl)-2-(4-chlo-ro-2-fluoro- phenyl)-1-meth- yl-propyl]-2-(4-fluoro-phenyloxy)-2-methyl- propanamide

4.5 492 isomer 3^(e) 132. N-[3-(4-Chloro- phenyl)-2-(4-fluoro-phenyl)-1-meth- yl-propyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

4.4 474 α 133. N-[3-(4-Chloro- phenyl)-2-(4-fluoro- phenyl)-1-meth-yl-propyl]-2-(4-chloro- phenyloxy)-2-meth- ylpropanamide

4.5 474 α:β 1:4 134. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-(2-py-ridyl)pro- pyl]-tert-butyl- carbamate^(f)

2.5 361 α 135. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-(2-py- ridyl)pro-pyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

3.0 457 α 136. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-(2-py- ridyl)pro-pyl]-2-(4-fluoro- phenyloxy)-2-methyl- propanamide

2.8 441 α 137. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-(4-py- ridyl)pro-pyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

2.9 457 α 138. N-[3-(4-Cyano- phenyl)-1-meth- yl-2-phenyl-propyl]-2-(3-chloro- phenyloxy)-2-methyl- propanamide

4.0 447 α 139. N-[3-(5-Chloro-2-py- ridyl)-1-meth- yl-2-phenyl-propyl]-2-(3,5-di- fluoro- phenyloxy)-2-methyl- propanamide

3.8 459 α 140. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-(3-py- ridyl)pro-pyl]-tert-butyl- carbamate^(f)

2.5 361 α 141. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-(3-py- ridyl)pro-pyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

3.0 457 α 142. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-(3-py- ridyl)pro-pyl]-2-(3,5-di- fluoro- phenyloxy)-2-methyl- propanamide

2.8 459 α 143. N-[3-(4-Chloro- phenyl)-1-meth- yl-2-(3-py- ridyl)pro-pyl]-2-(3-fluoro- phenyloxy)-2-methyl- propanamide

2.8 441 α 144. N-[2-(4-Chloro- phenoxy)-2-(4-chloro- phenyl)eth-yl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

4.2 479 — 145. N-[2,2-Bis(4-chloro- phenyl)ethyl]allyl- carbamate^(f)

3.9 350 — 146. N-[2,2-Bis(4-chloro- phenyl)eth- yl]-2-(4-chloro-phenyloxy)-2-methyl- propanamide^(f)

4.4 462 — 147. N-[2-(4-Chloro- phenyl- thio)-2-(4-chloro-phenyl)-1-methyl- propyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

4.8 508 α:β 2:3 148. N-[2-(4-Chloro- phenyl- thio)-2-(4-chloro-phenyl)-1-methyl- propyl]-2-(4-chloro- phenyloxy)-2-methyl- propanamide

4.8 508 β ^(a)For the synthesis of the acid starting material, seeEliel, EL J. Am. Chem. Soc. 1962, 84, 2371. ^(b)4-Chlorophenylisocyanatewas used in place of an acyl chloride. ^(c)Di(tert-butyl)dicarbonate wasused in place of an acyl chloride. ^(d)Isomer 1 is derived from Isomer 1of the amine (Reference Examples 21-22). ^(e)Isomers 2 and 3 are derivedfrom Isomers 2 and 3 of the amine (Reference Examples 21-22), and areseparated on silica gel. ^(f)Intermediates in the synthesis of thecorresponding amines.

EXAMPLES 149 and 150

N-[2,3-Bis(4-Chlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide(Diastereomer α, Enantiomers A and B)

Preparative HPLC was performed on a Gilson HPLC system for theseparation of enantiomers. Thus, a solution ofN-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide(Diastereomer α) (Example 60, 1.0 g) in hexane (3 mL)/ethanol (7 mL) wasloaded onto a Chiralpak AD column (2 cm×25 cm), which was eluted with 5%ethanol in hexane (flow rate 9 mL/min, 500 μL per injection) to give thetwo pure enantiomers.

Faster eluting enantiomer (Enantiomer A): Analytical HPLC: retentiontime=7.8 min (Chiralpak AD column, flow rate=0.75 mL/min, 5%ethanol/hexane). LC-MS: m/e 490 (M+H)⁺ (4.7 min).

Slower eluting enantiomer (Enantiomer B): Analytical HPLC: retentiontime=9.6 min (Chiralpak AD column, flow rate=0.75 mL/min, 5%ethanol/hexane). LC-MS: m/e 490 (M+H)⁺ (4.7 min).

EXAMPLES 151 and 152

N-[2,3-Bis(4-Chlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide(Diastereomer β, Enantiomers C and D)

Diastereomer β ofN-[2,3-bis(4-Chlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamidefrom Example 61 was separated on a CHIRALPAK AD column following theprocedure described for Examples 149-150 to give the faster elutingenantiomer (Enantiomer C) and the slower eluting enantiomer (EnantiomerD).

Faster eluting enantiomer (Enantiomer C): Analytical HPLC: retentiontime=8.0 min (Chiralpak AD column, flow rate=0.50 mL/min, 5%ethanol/hexane). LC-MS: m/e 490 (M+H)⁺ (4.7 min).

Slower eluting enantiomer (Enantiomer D): Analytical HPLC: retentiontime=12.6 min (Chiralpak AD column, flow rate=0.50 mL/min, 5%ethanol/hexane). LC-MS: m/e 490 (M+H)⁺ (4.7 min).

Examples 153-188 (Table 4) were isolated as single enantiomers followingthe procedures described in Examples 149-150 from the correspondingracemic material (Table 3) with appropriate modifications of (1) theeluent composition (4-15% ethanol/hexane), (2) flow rate (6-9 mL/min)and (3) injection volume (200 to 2000 μL).

TABLE 4 Enantiomeric compounds isolated according to the methodsdescribed in Examples 149-150. HPLC- retention mass Enan- Ex. timespectrum tiomer No. Name Structure (min) m/e A or B 153. N-[2,3-Bis(4-chlorophenyl)-1- methylpropyl]-2- phenyloxy)-2- methylpropanamide

4.5 456 A 154. N-[2,3-Bis(4- chlorophenyl)-1- methylpropyl]-2-phenyloxy-2- methylpropanamide

4.5 456 B 155. N-[2,3-Bis(4- chlorophenyl)-1- methylpropyl]-2-(4-fluorophenyloxy)-2- methylpropanamide

4.5 474 A 156. N-[2,3-Bis(4- chlorophenyl)-1- methylpropyl]-2-(4-fluorophenyloxy)-2- methylpropanamide

4.5 474 B 157. N-[2,3-Bis(4- chlorophenyl)-1- methylpropyl]-2-(6-methyl-3-pyridyloxy)-2- methylpropanamide

3.1 471 A 158. N-[2,3-Bis(4- chlorophenyl)-1- methylpropyl]-2-(6-methyl-3-pyridyloxy)-2- methylpropanamide

3.1 471 B 159. N-[3-(4-Chlorophenyl)- 1-methyl-2- phenylpropyl]-2-(3-fluorophenyloxy)-2- methylpropanamide

4.3 440 A 160. N-[3-(4-Chlorophenyl)- 1-methyl-2- phenylpropyl]-2-(3-fluorophenyloxy)-2- methylpropanamide

4.3 440 B 161. N-[3-(4-Chlorophenyl)- 1-methyl-2- phenylpropyl]-2-(3,4-difluorophenyloxy)-2- methylpropanamide

4.3 458 A 162. N-[3-(4-Chlorophenyl)- 1-methyl-2- phenylpropyl]-2-(3,4-difluorophenyloxy)-2- methylpropanamide

4.3 458 B 163. N-[3-(4-Chlorophenyl)- 1-methyl-2- phenylpropyl]-2-(3-chlorophenyloxy)-2- methylpropanamide

4.5 456 A 164. N-[3-(4-Chlorophenyl)- 1-methyl-2- phenylpropyl]-2-(3-chlorophenyloxy)-2- methylpropanamide

4.5 456 B 165. N-[3-(4-Chlorophenyl)- 1-methyl-2- phenylpropyl]-2-(3,5-difluorophenyloxy)-2- methylpropanamide

4.3 458 A 166. N-[3-(4-Chlorophenyl)- 1-methyl-2- phenylpropyl]-2-(3,5-difluorophenyloxy)-2- methylpropanamide

4.3 458 B 167. N-[3-(4-Chlorophenyl)- 1-methyl-2- phenylpropyl]-2-(4-fluorophenyloxy)-2- methylpropanamide

4.3 440 A 168. N-[3-(4-Chlorophenyl)- 1-methyl-2- phenylpropyl]-2-(4-fluorophenyloxy)-2- methylpropanamide

4.3 440 B 169. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(4- fluorophenyloxy)-2- methylpropanamide

4.4 474 A 170. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(4- fluorophenyloxy)-2- methylpropanamide

4.4 474 B 171. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(3,5- difluorophenyloxy)-2- methylpropanamide

4.3 476 A 172. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(3,5- difluorophenyloxy)-2- methylpropanamide

4.3 476 B 173. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(2- pyridyloxy)-2- methylpropanamide

3.9 440 A 174. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(2- pyridyloxy)-2- methylpropanamide

3.9 440 B 175. N-[3-(4-Chlorophenyl)- 1-methyl-2- phenylpropyl]-2-(2-pyridyloxy)-2- methylpropanamide

3.9 423 A 176. N-[3-(4-Chlorophenyl)- 1-methyl-2- phenylpropyl]-2-(2-pyridyloxy)-2- methylpropanamide

3.9 423 B 177. N-[3-(4-Chlorophenyl)- 1-methyl-2-(2-pyridyl)propyl]-2-(4- chlorophenyloxy)-2- methylpropanamide

3.0 457 A 178. N-[3-(4-Chlorophenyl)- 1-methyl-2-(2-pyridyl)propyl]-2-(4- chlorophenyloxy)-2- methylpropanamide

3.0 457 B 179. N-[3-(4-Cyanophenyl)- 1-methyl-2- phenylpropyl]-(3-chlorophenyloxy)-2- methylpropanamide

4.0 447 A 180. N-[3-(4-Cyanophenyl)- 1-methyl-2- phenylpropyl]-2-(3-chlorophenyloxy)-2- methylpropanamide

4.0 447 B 181. N-[3-(4-Chlorophenyl)- 1-methyl-2-(3-pyridyl)propyl]-2-(4- chlorophenyloxy)-2- methylpropanamide

3.0 457 A 182. N-[3-(4-Chlorophenyl)- 1-methyl-2-(3-pyridyl)propyl]-2-(4- chlorophenyloxy)-2- methylpropanamide

3.0 457 B 183. N-[3-(4-Chlorophenyl)- 1-methyl-2-(3-pyridyl)propyl]-2-(3,5- difluorophenyloxy)-2- methylpropanamide

2.8 459 A 184. N-[3-(4-Chlorophenyl)- 1-methyl-2-(3-pyridyl)propyl]-2-(3,5- difluorophenyloxy)-2- methylpropanamide

2.8 459 B 185. N-[3-(4-Chlorophenyl)- 1-methyl-2-(3-pyridyl)propyl]-2-(3- fluorophenyloxy)-2- methylpropanamide

2.8 441 A 186. N-[3-(4-Chlorophenyl)- 1-methyl-2-(3-pyridyl)propyl]-2-(3- fluorophenyloxy)-2- methylpropanamide

2.8 441 B 187. N-[2-(4- Chlorophenoxy)-2-(4- chlorophenyl)ethyl]-2-(4-chlorophenyloxy)-2- methylpropanamide

4.7 494 A 188. N-[2-(4- Chlorophenoxy)-2-(4- chlorophenyl)ethyl]-2-(4-chlorophenyloxy)-2- methylpropanamide

4.7 494 B

EXAMPLE 189

N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide

The title compound was prepared following the procedures described inExamples 62-63 substituting 2-amino-3,4-bis(4-chlorophenyl)butanehydrochloride salt withN-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine,hydrochloride (Reference Example 11). ¹H NMR (500 MHz, CD₃OD): δ 7.22(m, 2H), 7.16 (m, 1H), 7.06-7.02 (m, 4H), 6.76 (d, 2H), 6.62-6.54 (m,3H), 4.30 (m, 1H), 3.01 (dd, 1H), 2.83 (ddd, 1H), 2.95 (dd, 1H), 1.68(s, 3H), 1.62 (s, 3H), 0.88 (d, 3H). LC-MS: m/e 458 (M+H)⁺ (4.3 min).

Examples 190-194 (Table 5) were prepared following the proceduresdescribed in Examples 62-63 employingN-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine,hydrochloride from Reference Example 11 coupled to the appropriatecarboxylic acid.

TABLE 5 Single enantiomeric compounds prepared withN-[3-(4-chlorophenyl)-2(S)- phenyl-1(S)-methylpropyl]-amine,hydrochloride from Reference Example 11. HPLC- tention mass Ex. timespectrum No. Name Structure (min) m/e 190. N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)- methylpropyl]-2-(3,4,5- trifluorophenyloxy)-2-methylpropanamide

4.3 476 191. N-[3-(4-chlorophenyl)- 2(S)-phenyl-1(S)-methylpropyl]-2-(3-chloro- 4-fluorophenyloxy)-2- methylpropanamide

4.5 474 192. N-[3-(4-chlorophenyl)- 2(S)-phenyl-1(S)-methylpropyl]-2-(4-chloro- 3-fluorophenyloxy)-2- methylpropanamide

4.5 474 193. N-[3-(4-chlorophenyl)- 2(S)-phenyl-1(S)-methylpropyl]-2-(3,4- dichlorophenyloxy)-2- methylpropanamide

4.6 490 194. N-[3-(4-chlorophenyl)-2(S)- phenyl-1(S)-methylpropyl]-2-(3,5-dichlorophenyloxy)- 2-methylpropanamide

4.7 490

EXAMPLE 195

N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-3-hydroxy-2,2-dimethylpropanamide

To a mixture of 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt(Reference Example 1, Diastereomer α) (3.7 g, 11 mmol),3-hydroxy-2,2-dimethylpropionic acid (2.0 g, 17 mmol) in CH₂Cl₂ (100 mL)was added 1-hydroxybenzotriazole (2.3 g, 17 mmol), diisopropylethylamine(7.7 mL, 44 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide(3.2 g, 17 mmol). After stirring at room temperature overnight. Thereaction mixture was diluted with EtOAc (200 mL), washed with water andsaturated aqueous sodium bicarbonate, and concentrated to dryness, andthe residue was purified by flash column chromatography on silica geleluted with 50% EtOAc in hexane to give the title compound. ¹H NMR (500MHz, CD₃OD): δ 7.24 (d, 2H), 7.12 (d, 2H), 7.10 (d, 2H), 6.92 (d, 2H),4.25 (m, 1H), 3.68 (ABq, 2H), 3.18 (dd, 1H), 2.93 (ddd, 1H), 2.76 (dd,1H), 1.20 (s, 3H), 1.19 (s, 3H), 0.96 (d, 3H). LC-MS: m/e 394 (M+H)⁺(3.5 min).

EXAMPLE 196

N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-3-diethylamine-2,2-dimethylpropanamide

Step AN-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-formyl-2,2-dimethylpropanamide.

To a solution ofN-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-3-hydroxy-2,2-dimethylpropanamide(Example 193, 0.48 g, 1.2 mmol) in 20 mL CH₂Cl₂ was added crushedactivated molecular sieves (2 g). After stirring at room temperature for10 min, pyridinium chlorochromate (0.39 g, 1.8 mmol) was added. Afterstirring at room temperature for 1 h, CELITE diatomaceous earth (4 g)was added followed by 20 mL ether. The resulting mixture was filteredthrough a silica gel pad, which was washed with ether (2×20 mL). Thefiltrate was concentrated to dryness to give the title compound, whichwas used without further purification.

Step BN-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-3-diethylamino-2,2-dimethylpropanamide.

To a solution ofN-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-formyl-2,2-dimethylpropanamide(Step A, 37 mg, 0.094 mmol) and diethylamine (0.010 mL, 0.094 mmol) in 1mL 1,2-dichloroethane was added sodium triacetoxyborohydride (28 mg,0.13 mmol). After stirring at room temperature overnight, the reactionmixture was loaded onto a silica gel column eluted with 2% ammonia inMeOH (2 M) in EtOAc/hexane (1:1) to give the title compound. ¹H NMR (500MHz, CD₃OD): δ 7.24 (d, 2H), 7.12 (d, 2H), 7.10 (d, 2H), 6.96 (d, 2H),4.24 (m, 1H), 3.17 (dd, 1H), 3.00 (ddd, 1H), 2.80 (dd, 1H), 2.60 (q,4H), 1.22 (s, 3H), 1.18 (s, 3H), 0.99 (d, 3H), 0.98 (t, 6H). LC-MS: m/e449 (M+H)⁺ (3.2 min).

The compounds in Examples 197-199 were prepared following the proceduresdescribed in Example 196 substituting diethylamine with the appropriateamine.

EXAMPLE 197

N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-3-cyclopropylamino-2,2-dimethylpropanamide

LC-MS: m/e 433 (M+H)⁺ (3.0 min).

EXAMPLE 198

N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2,2-dimethyl-3-piperidinylpropanamide

¹H NMR (500 MHz, CD₃OD): δ 7.24 (d, 2H), 7.14 (d, 2H), 7.12 (d, 2H),6.96(d, 2H), 4.24 (m, 1H), 3.14 (dd, 1H), 3.00 (m, 1H), 2.82 (dd, 1H),2.62-2.40 (m, 4H), 1.62-1.3 (m, 6H), 1.22 (s, 3H), 1.16 (s, 3H), 1.00(d, 3H). LC-MS: m/e 461 (M+H) ⁺ (3.2 min).

EXAMPLE 199

N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-3-tert-butylamino-2,2-dimethylpropanamide

¹H NMR (500 MHz, CD₃OD): δ 7.24 (d, 2H), 7.12 (d, 2H), 7.08 (d, 2H),6.94 (d, 2H), 4.21 (m, 1H), 3.13 (dd, 1H), 2.98 (m, 1H), 2.81 (dd, 1H),1.22 (s, 3H), 1.20 (s, 3H), 1.12 (s, 9H), 0.98 (d, 3H). LC-MS: m/e 449(M+H)⁺ (3.2 min).

EXAMPLE 200

N-[2,3-Bis(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenylamino)-2-methylpropanamide

To a mixture of 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt(Diastereomer α, Section I, Reference Example 1, 0.31 g, 0.94 mmol) and2-(4-chlorophenylamino)-2-methylpropionic acid (0.20 g, 0.94 mmol) in 5mL CH₂Cl₂ was added N-methylmorpholine (0.41 mL, 3.5 mmol) andtris(pyrrolindinyl) phosphonium hexafluorophosphate (0.73 g, 1.4 mmol).After stirring at RT overnight, the reaction mixture was loaded onto asilica gel column eluted with 30% EtOAc in hexane to give the titlecompound. ¹H NMR (400 MHz, CD₃OD): δ 7.18 (d, 2H), 7.04 (d, 2H), 7.02(d, 2H), 6.97 (d, 2H), 6.70 (d, 2H), 6.56 (d, 2H), 4.20 (m, 1H), 3.02(dd, 1H), 2.78 (ddd, 1H), 2.64 (dd, 1H), 1.52 (s, 3H), 1.45 (s, 3H),0.82 (d, 3H). LC-MS: m/e 489 (M+H)⁺ (4.3 min).

EXAMPLE 201

N-[3-(4-Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-pyridyloxy-N-oxide)-2-methylpropanamide

To a solutionN-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-pyridyloxy)-2-methylpropanamide(Example 102, 83 mg, 0.20 mmol) in 1 mL CH₂Cl₂ was addedm-chloroperbenzoic acid (50%, 0.10 g, 0.30 mmol). After stirring at roomtemperature for 1 h, the reaction mixture was concentrated to dryness,and the residue was dissolved in DMSO, acetonitrile and water (2:2:1, 2mL) and loaded onto a reverse-phase semi-preparative HPLC column elutedwith 75% water/acetonitrile (0.1% trifluoroacetic acid) to 100%acetonitrile (0.1% trifluoroacetic acid) to give the title compound. ¹HNMR (500 MHz, CD₃OD): δ 8.16 (m, 1H), 8.05 (dd, 1H), 7.47 (dd, 1H), 7.28(dd, 1H), 7.22 (m, 2H), 7.15 (m, 1H), 7.04 (d, 4H), 6.78 (d, 2H), 4.30(m, 1H), 2.99 (dd, 1H), 2.88 (ddd, 1H), 2.74 (dd, 1H), 1.71 (s, 3H),1.66 (s, 3 H), 0.88 (d, 3H). LC-MS: m/e 439 (M+H)⁺ (3.0 min).

EXAMPLE 202

N-[3-(4-Chlorophenyl)-1-methyl-2-(3-pyridyl-N-oxide)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide(Diastereomer α, Enantiomer B)

N-[3-(4-Chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide(Example 182) was converted to the title compound following theprocedure described in Example 201. LC-MS: m/e 473 (M+H)⁺ (3.2 min).

EXAMPLE 203

N-[3-(4-Chlorophenyl)-1-methyl-2-(3-pyridyl-N-oxide)propyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide(Diastereomer α, Enantiomer A)

N-[3-(4-Chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide(Example 181) was converted to the title compound following theprocedure described in Example 201. LC-MS: m/e 475 (M+H)⁺ (3.1 min).

EXAMPLE 204

N-[3-(4-Chlorophenyl)-1-methyl-2-(3-pyridyl-N-oxide)propyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide(Diastereomer α, Enantiomer B)

N-[3-(4-Chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide(Example 184) was converted to the title compound following theprocedure described in Example 201. LC-MS: m/e 475 (M+H)⁺ (3.1 min).

EXAMPLE 205

N-[3-(4-Chlorophenyl)-1(S)-methyl-2(S)-phenylpropyl]-2-(4-chloro-3,5-difluorphenyloxy)-2-methylpropanamide

A solution ofN-[(3-(4-chlorophenyl)-1(S)-methyl-2(S)-phenylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide (Example 189, 0.20 g, 0.43 mmol) in anhydrous THF (1mL) was added dropwise to a solution of sec-butyl lithium (1.3 M incyclohexane, 0.84 mL, 1.1 mmol) and N,N,N′,N′-tetramethylethylenediamine(0.16 mL, 1.1 mmol) in 1 mLTHF at −78° C. After stirring at −78° C.under nitrogen for 1 h, a solution of N-chlorosuccinimide (0.13 g, 0.86mmol) in 4 mL THF was added at −7 ° C. After stirring at −78° C. foranother hour, the reaction mixture was poured into saturated aqueousammonium chloride (50 mL), and the product was extracted with EtOAc(3×50 mL). The combined extracts were dried over anhydrous sodiumsulfate, filtered and concentrated to dryness, and the residue waspurified by flash column chromatography eluted with 10% EtOAc in hexaneto give the title compound. ¹H NMR (500 MHz, CD₃OD): δ 7.3-6.5 (m, 11H),4.29 (m, 1H), 2.97 (dd, 1H), 2.84 (m, 1H), 2.70 (dd, 1H), 1.67 (s, 3H),1.62 (s, 3H), 0.88 (d, 3 H). LC-MS: m/e 492 (M+H)⁺ (4.5 min).

EXAMPLE 206

N-[3-(R)-(4-Chlorophenyl)-1(S),3-dimethyl-2(S)-phenylbutyl]-2-(3,5-difluoro-4-methylphenyloxy)-2-methylpropanamideandN-[3(S)-(3-Chlorophenyl)-1(S),3-dimethyl-2(S)-phenylbutyl]-2-(3,5-difluoro-4-methylphenyloxy)-2-methylpropanamide(2 Isomers)

A solution ofN-[(2S,3S)-3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide(Example 187, 0.20 g, 0.43 mmol) in anhydrous THF (1 mL) was addeddropwise to a solution of sec-butyl lithium (1.3 M in cyclohexane, 0.84mL, 1.1 mmol) and N,N,N′N′-tetramethylethylenediamine (0.16 mL, 1.1mmol) in 1 mL THF at −78° C. After stirring at −78° C. under nitrogenfor 1 h, methyl iodide (0.11 mL, 1.7 mmol) was added at −78° C. Afterstirring at −78° C. for another hour, the reaction mixture was pouredinto saturated aqueous ammonium chloride (50 mL), and the product wasextracted with EtOAc (3×50 mL). The combined extracts were dried overanhydrous sodium sulfate, filtered and concentrated to dryness, and theresidue was purified by flash column chromatography on silica gel elutedwith 10% EtOAc in hexane to give the title compound as a 1:1 mixture ofdiastereomers. Further purification by reverse-phase HPLC afforded thepure diastereomers.

Faster eluting diastereomer: ¹H NMR (500 MHz, CD₃OD): δ 7.3-6.5 (m,11H), 4.46 (m, 1H), 3.26 (m, 1H), 3.03 (dd, 1H), 2.09 (s, 3H), 1.62 (s,3H), 1.55 (s, 3H), 1.29 (d, 3H), 0.97 (d, 3H). LC-MS: m/e 486 (M+H)⁺(4.7 min).

Slower eluting diastereomer (14 mg): ¹H NMR (500 MHz, CD₃OD): δ7.28-7.18 (m, 5H), 7.02-6.94 (m, 4H), 6.48 (d, 2H), 4.27 (m, 1H), 3.13(m, 1H), 2.98 (dd, 1H), 2.03 (s, 3H), 1.57 (s, 3H), 1.51 (s, 3H), 1.04(d, 3H), 0.93 (d, 3H). LC-MS: m/e 486 (M+H)⁺ (4.8 min).

EXAMPLE 207

N-[2,3-Bis(4-Chlorophenyl)-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide(Diastereomer α)

Step A Ethyl 2-(4-Methyl-3-pyridyloxy)-2-methylpropionate.

To a solution of ethyl 2-(6-methyl-3-pyridyloxy)acetate (5.0 g, 26 mmol)and methyl iodide (6.3 mL, 0.10 mol) in 100 mL anhydrous THF at −78° C.was added potassium tert-butoxide (1 M in THF, 50 mL, 50 mmol), and thereaction was allowed to warm to room temperature overnight. The reactionmixture was poured into saturated ammonium chloride (200 mL), and theproduct was extracted with EtOAc (2×150 mL). The combined extracts weredried over anhydrous MgSO₄, filtered and concentrated to dryness, andthe residue was purified by flash column chromatography eluted with 4:1to 2:1 hexane/EtOAc to give the title compound. ¹H NMR (500 MHz, CD₃OD):δ 8.04-8.00 (m, 1H), 7.28-7.18 (m, 2H), 4.77 (q, 2H), 2.45 (s, 3H), 1.44(s, 6H), 1.24 (t, 3H).

Step B 2-(6-Methyl-3-pyridyloxy)-2-methylpropionic Acid

To a solution of ethyl 2-(6-methyl-3-pyridyloxy)-2-methylpropionate(Step A, 2.0 g, 8.9 mmol) in DMSO (20 mL) was added potasium hydroxide(1.0 g, 20 mmol) in 2 mL water. After stirring at room temperature for 2h, the reaction was quenched by addition of formic acid (85%, 10 mmol)and poured into water (200 mL). The product was extracted with EtOAc(2×100 mL), and the combined extracts were dried over anhydrous sodiumsulfate, filtered and concentrated to dryness to give the title compoundcontaminated with DMSO (molar ratio 1:5, determined by NMR). ¹H NMR (500MHz, CD₃OD): δ 8.06 (d, 1H), 7.38-7.22 (m, 2H), 2.47 (s, 3H), 1.58 (s,6H).

Step CN-[2,3-Bis(4-Chlorophenyl)-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide(Diastereomer α)

The title compound was prepared by reacting2-(6-methyl-3-pyridyloxy)-2-methylpropionic acid (Step B, 75 mg, 0.63mmol) with 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt(Diastereomer α, Reference Example 1) (0.23 g, 0.63 mmol) following theprocedure described in Example 62-63. LC-MS: m/e 471 (M+H)⁺ (3.1 min).

EXAMPLE 208

N-[3-(4-Chlorophenyl)-2-phenyl-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide(Diastereomer β)

The title compound was prepared following the procedures described inExample 207 substituting 2-amino-3,4-bis(4-chlorophenyl)butanehydrochloride salt with 2-amino-3-(4-chlorophenyl)-2-phenylbutanehydrochloride salt (Diastereomer β, Reference Example 5)) at Step C.LC-MS: m/e 437 (M+H)⁺ (2.8 min).

EXAMPLE 209

N-(1,4-dimethyl-2-phenylpentyl)-2-(4-chlorophenoxy)-2-methylpropanamide

2-Amino-5-methyl-3-phenylhexane hydrochloride salt from ReferenceExample 26 (30 mg) was reacted with the acid chloride prepared from of2-(4-chlorophenoxy)-2-methyl-propionic acid (37 mg) according to theprocedure described in Example 62-63 to afford the title compound afterpurification by preparative TLC on silica gel eluted with 20%EtOAC-hexane. ¹H NMR: (500 MHz, CDCl₃): δ 0.83 and 0.85 (2d, 6H), 0.96(d, 3H), 1.34 (m, 1H), 1.45 (m, 1 H), 1.53 (s, 3H), 1.59 (s, 3H), 2.73(m, 1H), 4.24 (m, 1H), 6.41 (d, 1H), 6.8-7.4 (m, 9H). LC-MS: R_(t)=4.5min. m/e=388.3 (M+1).

The following compounds in Table 6 were prepared following the procedureof Example 209 substituting appropriate amine for2-amino-5-methyl-3-phenylhexane and appropriate carboxylic acid for2-(4-chlorophenoxy)-2-methyl-propionic acid.

TABLE 6 retention HPLC-mass Ex. time spectrum No. Name Structure (min)m/e 210. N-(1-methyl-2- phenylpentyl)-2-(4- chlorophenoxy)- acetamide

4.4 374.1 211. N-(1-methyl-2,5- diphenylpentyl)-2-(4- chlorophenoxy)-acetamide

4.7 450.3 212. N-(1,3-dimethyl-2- phenylbutyl)-2-(4- chlorophenoxy)-propanamide

4.4 374.2

EXAMPLE 213

N-(2,3-Diphenyl-1-methylpropyl)-2-(4-chlorophenoxy)-2-methylpropanamide(Diastereomer β)

A solution of 2-(4-chlorophenoxy)-2-methylpropionic acid (20 mg, 0.095mmol) in CH₂Cl₂ (1 mL) and DMF (10 μL) was treated with oxalyl chloride(11 μL). After 30 min the reaction was concentrated and the residue wasdissolved in 1 mL CH₂Cl₂. This solution was added to a mixture of 16 mgN-(2,3-diphenyl-1-methylpropylamine (β isomer from Reference Example 2)and 1 mL saturated NaHCO₃. The reaction was stirred overnight and theorganic layer was removed with a pipet. Purification of this solution bypreparative TLC eluted with 30% EtOAc/hexane afforded the titlecompound. ¹H NMR: (500 MHz, CDCl₃): δ 1.17 (d, 3H), 1.36 (s, 3H), 1.46(s, 3H), 2.85-3.05 (m, 3H), 4.44 (m, 1H), 6.37 (d, 1H), 6.75-7.4 (m,14H). LC-MS: R_(t)=4.4 min. m/e=422.2 (M+1).

EXAMPLE 214

N-(2,3-Diphenyl-1-methylpropyl)-2-(4-chlorophenoxy)-2-methylpropanamide(Diastereomer α)

Reaction of 16 mg N-(2,3-diphenyl)-1-methylpropylamine (α isomer,Reference Example 2) with the acid chloride prepared from 20 mg2-(4-chlorophenoxy)-2-methylpropionic acid as described in example 213gave the title compound. ¹H NMR: (500 MHz, CDCl₃): δ 1.02 (d, 3H), 1.51(s, 3H), 1.57 (s, 3H), 2.9-3.2 (m, 3H), 4.37 (m, 1H), 6.51 (d, 1H),6.8-7.4 (m, 14H). LC-MS: R_(t)=4.3 min. m/e=422.3 (M+1).

EXAMPLES 215 and 216

N-(2,3-Diphenyl-1-methylpropyl)-2-(4-chlorophenoxy)-2-methylpropanamide(Diastereomer β, Enantiomers A and B)

The racemicN-(2,3-diphenyl-1-methylpropyl)-2-(4-chlorophenoxy)-2-methylpropanamide(Diastereomer β, Example 213) was resolved on a Chiralcel OD columnusing 5% EtOH/hexane as an eluant at a flow rate of 7 mL/min on HPLC.The respective enantiomers of the title compound had retention times of9.85 min and 13.17 min on an analytical Chiralcel OD (4.6×250 mm) columnusing 5% EtOH/hexane at 0.5 mL/min.

Faster eluting isomer A: ¹H NMR: (500 MHz, CDCl₃): δ 1.16 (d, 3H), 1.36(s, 3H), 1.46 (s, 3H), 2.89 (m, 1H), 2.97 (m, 1H), 3.09 (m, 1H), 4.44(m,1H), 6.36 (d, 1H), 6.75 (m, 2H), 7.0-7.4 (m, 12H).

Slower eluting isomer B: ¹H NMR: (500 MHz, CDCl₃): δ 1.16 (d, 3H), 1.36(s, 3H), 1.46 (s, 3H), 2.89 (m, 1H), 2.97 (m, 1H), 3.09 (m, 1H), 4.44(m,1H), 6.36 (d, 1H), 6.75 (m, 2H), 7.0-7.4 (m, 12H).

EXAMPLES 217 and 218

N-(2,3-Diphenyl-1-methylpropyl)-2-(4-chlorophenoxy)-2-methylpropanamide(Diastereomer α, Enantiomers A and B)

Resolution ofN-(2,3-diphenyl-1-methylpropyl)-2-(4-chlorophenoxy)-2-methylpropanamide(Diastereomer α, Example 214) was carried out on a Chiralcel OD columnas detailed in Example 215-216 to afford the respective enantiomers.

Faster eluting enantiomer A (Rt=13.8 min): ¹H NMR: (500 MHz, CDCl₃): δ1.01 (d, 3H), 1.51 (s, 3H), 1.57 (s, 3H), 2.97 (m, 2H), 3.1 (m, 1H),4.37 (m, 1H), 6.5 (d, 1H), 6.8-7.4 (m, 14H).

Slower eluting enantiomer B (R_(t)=21.6 min): ¹H NMR: (500 MHz, CDCl₃):δ 1.01 (d, 3H), 1.51 (s, 3H), 1.57 (s, 3H), 2.97 (m, 2H), 3.1 (m, 1H),4.37(m, 1H), 6.5 (d, 1H), 6.8-7.4 (m, 14H).

EXAMPLE 219

N-(2,3-Diphenyl-1-ethylpropyl)-2-(4-chlorophenoxy)-2-methylpropanamide

N-(2,3-diphenyl)-1-ethylpropylamine (Reference Example 3) was reactedwith the acid chloride derived from2-(4-chlorophenoxy)-2-methylpropionic acid according to the proceduresdescribed in Example 213 to afford the title compound as a mixture ofdiastereomers. ¹H NMR: (500 MHz, CDCl₃): δ 0.82 (t, 3H), 1.16 (m, 1H),1.57 (s, 3H), 1.60 (s, 3H), 2.95 (m, 2H), 3.14 (m, 1H), 4.25(m, 1H), 6.5(d, 1H), 6.8-7.4 (m, 14H). LC-MS: R_(t)=4.5 min. m/e=436.2 (M+1).

The following compounds in Table 7 were prepared following theprocedures of Example 213 substituting an appropriate amine forN-(2,3-diphenyl-1-methylpropylamine and appropriate carboxylic acid for2-(4-chlorophenoxy)-2-methyl-propionic acid.

TABLE 7 HPLC- retention mass Ex. time spectrum No. Name Structure (min)m/e 220. N-(3-(4-chlorophenyl)-2- phenyl-1-methylpropyl)-2-(4-chlorophenoxy)- acetamide

4.2 428.0 221. N-(2,3-diphenyl-1- methylpropyl)-2-(4- chlorophenoxy)-acetamide

4.0 394.1 222. N-(3-(4-chlorophenyl)-2- phenyl-1-methylpropyl)-2-(4-chlorophenoxy)- propanamide

4.2 442.1 223. N-(2,3-diphenyl-1- methylpropyl)-2-(4- chlorophenoxy)propanamide

4.0 408.2 224. N-(2,3-bis(4- chlorophenyl)-1- methylpropyl)-2-methyl-3-phenyl-propanamide (Isomer A)

4.2 440.2 225. N-(2,3-bis(4- chlorophenyl)-1- methylpropyl)-2-methyl-3-phenyl-propanamide (Isomer B)

4.3 440.3 226. N-(2,3-bis(4- chlorophenyl)-1- methylpropyl)-2-methyl-3-(4-chlorophenyl)- propanamide (Isomer A)

4.3 4.4 476.1 227. N-(2,3-bis(4- chlorophenyl)-1-methylpropyl)-2-methyl- 3-(4-chlorophenyl)- propanamide (Isomer B)

4.3 4.5 474.2 228. N-(3-(4-chlorophenyl)-2- phenyl-1-methylpropyl)-2-(4-chloro-anilino)- acetamide

3.8 393.1 229. N-(2,3-diphenyl-1- methylpropyl)-2-(4- chloro-anilino)-acetamide

3.5 359.2 230. N-(2,3-bis(4- chlorophenyl)-1- methylpropyl)-2,2-dimethyl-3-phenyl- propanamide

4.5 454.2 231. N-(3-(4-chlorophenyl)-2- phenyl-1-methylpropyl)-2-methyl-2-(4- chlorophenoxy)- propanamide

4.5 456.0 232. N-(3-(2-chlorophenyl)-2- phenyl-1-methylpropyl)-2-methyl-2-(4- chlorophenoxy)- propanamide

4.5 456.2 233. N-(3-(4- trifluoromethylphenyl)-2-phenyl-1-methylpropyl)- 2-methyl-2-(4- chlorophenoxy)- propanamide

4.5 490.1 234. N-(3-(4-fluorophenyl)-2- phenyl-1-methylpropyl)-2-methyl-2-(4- chlorophenoxy) propanamide

4.3 440.2 235. N-(3-(4-chlorophenyl)-2- phenyl-1-methylpropyl)-2-methyl-2-phenoxy- propanamide

4.3 422.2 236. N-(3-(4-chlorophenyl)-2- phenyl-1-methylpropyl)-2-methyl-2-(4- fluorophenoxy)- propanamide

4.2 440.1 237. N-(2,3-diphenyl-1- methylpropyl)-2-methyl-2-(4-fluorophenoxy)- propanamide

4.1 406.2 238. N-(3-phenyl-2-benzyl-1- methylpropyl)-2-methyl-2-(4-chlorophenoxy)- propanamide

4.6 436.2

The following compounds in Table 8 were prepared following theprocedures of Examples 62-63 substituting an appropriate amine forN-(2,3-diphenyl-1-methylpropylamine and appropriate carboxylic acid for2-(4-chlorophenoxy)-2-methyl-propionic acid.

TABLE 8 Compounds prepared according to the methods described inExamples 62-63. Diaster- retention HPLC-mass eomer Ex. time spectrum αand/or No. Name Structure (min) m/e β 239. N-[3-(4-Chlorophenyl)-2-(3,5-difluorophenyl)- 1-methylpropyl]-2-(3,5- difluorophenyloxy)-2-methylpropanamide

4.3 494 α 240. N-[3-(4-Chlorophenyl)- 2-(3,5-difluorophenyl)-1-methylpropyl]-2- methyl-2-(3,4,5- trifluorophenyloxy)pro- panamide

4.4 512 α 241. N-[3-(4-Chlorophenyl)- 2-(3,5-difluorophenyl)-1-methylpropyl]-2- methyl-2-(2- pyridyloxy)propanamide

3.9 459 α 242. N-[3-(4-Chlorophenyl)- 2-(3,5-difluorophenyl)-1-methylpropyl]-2-(4- chlorophenyloxy)-2- methylpropanamide

4.4 492 α 243. N-[3-(4-Chlorophenyl)- 2-(3-pyridyl)-1-methylpropyl]-2-(3,5- dichlorophenyloxy)-2- methylpropanamide

3.0 491 α 244. N-[3-(4-Chlorophenyl)- 2-(3-pyridyl)-1-methylpropyl]-2-(3- chlorophenyloxy)-2- methylpropanamide

2.9 457 α 245. N-[3-(4-Chlorophenyl)- 2-(3-pyridyl)-1-methylpropyl]-2-(3- chloro-5- fluorophenyloxy)-2- methylpropanamide

3.0 475 α 246. N-[3-(4-Chlorophenyl)- 2-(3-pyridyl)-1-methylpropyl]-2-methyl- 2-(2- pyridyloxy)propanamide

2.4 424 α 247. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(3- chloro-5- fluorophenyloxy)-2- methylpropanamide

4.5 492 α 248. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(3- chlorophenyloxy)-2- methylpropanamide

4.4 474 α 249. N-[3-(4-Chlorophenyl)- 2-(3-cyanophenyl)-1-methylpropyl]-2-(3- chlorophenyloxy)-2- methylpropanamide

4.1 481 α 250. N-[3-(4-Chlorophenyl)- 2-(3-cyanophenyl)-1-methylpropyl]-2-methyl- 2-(2- pyridyloxy)propanamide

3.6 448 α 251. N-[2-(3-Chlorophenyl)- 3-(4-chlorophenyl)-1-methylpropyl]-2-methyl- 2-(2- pyridy1oxy)propanamide

4.2 457 α

The following compounds in Table 9 were isolated according to theprocedures for separating enantiomers described in Examples 149-150.

TABLE 9 Enantiomeric compounds isolated according to the methodsdescribed in Examples 149-150. HPLC- retention mass Enan- Ex. timespectrum tiomer No. Name Structure (min) m/e A or B 251.N-[3-(4-Chlorophenyl)-2- (3,5-difluorophenyl)-1- methylpropyl]-2-(3,5-difluorophenyloxy)-2- methylpropanamide

4.3 494 A 252. N-[3-(4-Chlorophenyl)-2- (3,5-difluorophenyl)-1-methylpropyl]-2-(3,5- difluorophenyloxy)-2- methylpropanamide

4.4 494 B 253. N-[3-(4-Chlorophenyl)-2- (3,5-difluorophenyl)-1-methylpropyl]-2-methyl-2- (3,4,5- trifluorophenyloxy)propana- mide

4.4 512 A 254. N-[3-(4-Chlorophenyl)-2- (3,5-difluorophenyl)-1-methylpropyl]-2-methyl-2- (3,4,5- trifluorophenyloxy)propana- mide

4.4 512 B 255. N-[3-(4-Chlorophenyl)-2- (3,5-difluorophenyl)-1-methylpropyl]-2-(4- chlorophenyloxy)-2- methylpropanamide

4.5 492 A 256. N-[3-(4-Chlorophenyl)-2- (3,5-difluorophenyl)-1-methylpropyl]-2-(4- chlorophenyloxy)-2- methylpropanamide

4.5 492 B 257. N-[3-(4-Chlorophenyl)-2- (3,5-difluorophenyl)-1-methylpropyl]-2-methyl-2- (2-pyridyloxy)propanamide

3.9 459 A 258. N-[3-(4-Chlorophenyl)-2- (3,5-difluorophenyl)-1-methylpropyl]-2-methyl-2- (2-pyridyloxy)propanamide

3.9 459 B 259. N-[3-(4-Chlorophenyl)-2- (3-pyridyl)-1-methylpropyl]-2-(3,5- dichlorophenyloxy)-2- methylpropanamide

3.2 491 A 260. N-[3-(4-Chlorophenyl)-2- (3-pyridyl)-1-methylpropyl]-2-(3,5- dichlorophenyloxy)-2- methylpropanamide

3.2 491 B 261. N-[3-(4-Chlorophenyl)-2- (3-pyridyl)-1-methylpropyl]-2-(3- chlorophenyloxy)-2- methylpropanamide

2.9 457 A 262. N-[3-(4-Chlorophenyl)-2- (3-pyridyl)-1-methylpropyl]-2-(3- chlorophenyloxy)-2- methylpropanamide

2.9 457 B 263. N-[2-(3-Bromophenyl)-3- (4-chlorophenyl)-1-methylpropyl]-2-methyl-2- (2-pyridyloxy)propanamide

4.09 501 A 264. N-[2-(3-Bromophenyl)-3- (4-chlorophenyl)-1-methylpropyl]-2-methyl-2- (2-pyridyloxy)propanamide

4.09 501 B 265. N-[2-(3-Bromophenyl)-3- (4-chlorophenyl)-1-methylpropyl]-2-methyl-2- (2-pyridyloxy)propanamide

4.2 501/549 A and N-[3-(4-chlorophenyl)- 2-(3-iodophenyl)-1-methylpropyl]-2-methyl-2- (2-pyridyloxy)propanamide (1:1 mixture)

266. N-[2-(3-Bromophenyl)-3- (4-chlorophenyl)-1-methylpropyl]-2-methyl-2- (2-pyridyloxy)propanamide

4.2 501/549 B and N-[3-(4-chlorophenyl)- 2-(3-iodophenyl)-1-methylpropyl]-2-methyl-2- (2-pyridyloxy)propanamide (1:1 mixture)

267. N-[2-(3-Bromophenyl)-3- (4-chlorophenyl)-1-methylpropyl]-2-methyl-2- (2-phenyloxy)propanamide

4.4 500 A 268. N-[2-(3-Bromophenyl)-3- (4-chlorophenyl)-1-methylpropyl]-2-methyl-2- (2-phenyloxy)propanamide

4.4 500 B 269. N-[3-(4-Chlorophenyl)-2- (3-pyridyl)-1-methylpropyl]-2-methyl-2- (2-pyridyloxy)propanamide

2.5 424 A 270. N-[3-(4-Chlorophenyl)-2- (3-pyridyl)-1-methylpropyl]-2-methyl-2- (2-pyridyloxy)propanamide

2.5 424 B 271. N-[3-(4-Chlorophenyl)-2- (3-fluorophenyl)-1-methylpropyl]-2-(3-chloro- 5-fluorophenyloxy)-2- methylpropanamide

4.6 492 A 272. N-[3-(4-Chlorophenyl)-2- (3-fluorophenyl)-1-methylpropyl]-2-(3-chloro- 5-fluorophenyloxy)-2- methylpropanamide

4.6 492 B 273. N-[3-(4-Chlorophenyl)-2- (3-fluorophenyl)-1-methylpropyl]-2-(3- chlorophenyloxy)-2- methylpropanamide

4.4 474 A 274. N-[3-(4-Chlorophenyl)-2- (3-fluorophenyl)-1-methylpropyl]-2-(3- chlorophenyloxy)-2- methylpropanamide

4.4 474 B 275. N-[3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-(3- chlorophenyloxy)-2- methylpropanamide

4.3 481 A 276. N-[3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-(3- chlorophenyloxy)-2- methylpropanamide

4.3 481 B 277. N-[3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- (2-pyridyloxy)propanamide

3.8 448 A 278. N-[3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- (2-pyridyloxy)propanamide

3.8 448 A 279. N-[2-(3-Chlorophenyl)-3- (4-chlorophenyl)-1-methylpropyl]-2-methyl-2- (2-pyridyloxy)propanamide

4.0 457 A 280. N-[2-(3-Chlorophenyl)-3- (4-chlorophenyl)-1-methylpropyl]-2-methyl-2- (2-pyridyloxy)propanamide

4.0 457 BA

The following compounds in Table 10 were prepared withN-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine,hydrochloride from Reference Example 11 and the appropriate acid toafford a single enantiomer.

TABLE 10 Single enantiomeric compounds prepared withN-[3-(4-chlorophenyl)-2(S)- phenyl-1(S)-methylpropyl]-amine,hydrochloride. HPLC- retention mass Ex. time spectrum No. Name Structure(min) m/e 281. N-[(2S,3S)-3-(4- Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(5- chloropyridyloxy)-2- methylpropanamide

4.2 457 282. N-[(2S,3S)-3-(4- Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(6- methylpyndyloxy)-2- methylpropanamide

3.8 437 283. N-[(2S,3S)-3-(4- Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-chloro-5- fluorophenyloxy)-2- methylpropanamide

4.6 474 284. N-[(2S,3S)-3-(4- Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3- pyridazinyloxy)-2- methylpropanamide

3.4 424 285. N-[(2S,3S)-3-(4- Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4- trifluoromethylphenyloxy)-2- methylpropanamide

4.5 490 286. N-[(2S,3S)-3-(4- Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(5- trifluoromethylpyridyloxy)-2- methylpropanamide

4.3 491 287. N-[(2S,3S)-3-(4- Chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4,6- dimethylpyridyloxy)-2- methylpropanamide

3.8 451

The following compounds in Table 11 were prepared according to theprocedures of Example 200 substituting an appropriate amine forN-(2,3-diphenyl-1-methylpropylamine and an appropriate carboxylic acidfor 2-(4-chlorophenoxy)-2-methyl-propionic acid.

TABLE 11 HPLC- retention mass Ex. time spectrum No. Name Structure (min)m/e 288. N-(3-(4-chlorophenyl)-2- cyclopentyl-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2- methylpropanamide (Diastereomer A)

5.3^(a) 484.0 289. N-(3-(4-chlorophenyl)-2- cyclopentyl-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2- methylpropanamide (Diastereomer B)

5.3^(b) 484.0 290. N-(3-(4-chlorophenyl)-2- cyclopentyl-1-methyl)propyl-2-(3,5-difluorophenoxy)-2- methylpropanamide(Diaster- eomer A)

4.9^(a) 450.1 291. N-(3-(4-chlorophenyl)-2- cyclopentyl-1-methyl)propyl-2-(3,5-difluorophenoxy)-2- methylpropanamide(Diaster- eomer B)

4.9^(b) 450.1 292. N-(3-(4-chlorophenyl)-2- ethoxy-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2- methylpropanamide(Diaster- eomer A)

4.7 460.0 293. N-(3-(4-chlorophenyl)-2- ethoxy-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2- methylpropanamide(Diaster- eomer B)

4.6 460.0 294. N-(3-(4-chlorophenyl)-2- isopropyl-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2- methylpropanamide

4.9 458.0 295. N-(3-(4-chlorophenyl)-1- methyl-2-propoxy)propyl-2-(3,5-dichlorophenoxy)-2- methylpropanamide(Diaster- eomer A)

4.9 474.0 296. N-(3-(4-chlorophenyl)-1- methyl-2-propoxy)propyl-2-(3,5-dichlorophenoxy)-2- methylpropanamide(Diaster- eomer B)

4.8 474.0 297. N-(3-(4-chlorophenyl)-1- methyl-2-pentoxy)propyl-2-(3,5-dichlorophenoxy)-2- methylpropanamide(Diaster- eomer A)

5.3 502.0 298. N-(3-(4-chlorophenyl)-1- methyl-2-pentoxy)propyl-2-(3,5-dichlorophenoxy)-2- methylpropanamide(Diaster- eomer B)

5.1 502.0 299. N-(3-(4-chlorophenyl)-2- cyclopentylmethoxy-1-methyl)propyl-2-(3,5- dichlorophenoxy)-2- methylpropanamide(Diaster-eomer A)

5.3 514.0 300. N-(3-(4-chlorophenyl)-2- cyclopentylmethoxy-1-methyl)propyl-2-(3,5- dichlorophenoxy)-2- methylpropanamide(Diaster-eomer B)

5.2 514.0 301. N-(3-(4-chlorophenyl)-2- cyclobutylmethoxy-1-methyl)propyl-2-(3,5- dichlorophenoxy)-2- methylpropanamide(Diaster-eomer A)

5.1^(a) 500.0 302. N-(3-(4-chlorophenyl)-2- cyclobutylmethoxy-1-methyl)propyl-2-(3,5- dichlorophenoxy)-2- methylpropanamide(Diaster-eomer B)

5.1^(b) 500.0 303. N-(3-(4-chlorophenyl)-2-ethyl-1-methyl)propyl-2-(3,5- dichlorophenoxy)-2- methylpropanamide

4.8 443.8 304. N-(3-(4-chlorophenyl)-2- ethyl-1-methyl)propyl-2-(3,5-difluorophenoxy)-2- methylpropanamide

4.4 410.8 305. N-(3-(4-chlorophenyl)-2- methoxy-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2- methylpropanamide (Diastereomer A)

4.6 445.8 306. N-(3-(4-chlorophenyl)-2- methoxy-1-methyl)propyl-2-(3,5-dichlorophenoxy)-2- methylpropanamide (Diastereomer B)

4.5 445.8 307. N-(3-(4-chlorophenyl)-2- pyrrolidin-N-yl-1-methyl)propyl-2-(3,5- dichlorophenoxy)-2- methylpropanamide

3.3 3.5 484.9 308. N-(3-(4-chlorophenyl)-2- benzyloxycarbonyl-1-methyl)propyl-2-(3,5- dichlorophenoxy)-2- methylpropanamide

4.6 4.7 548.0 ^(a)The less polar pair of diastereomers. ^(b)The morepolar pair of diastereomers.

EXAMPLE 309

N-(2-(1-(1,2,3-triazolyl))-3-(4-chlorophenyl)-1-methylpropyl)-2-(4-chlorophenyloxy)-2-methylpropanamide

A mixture of 2-amino-3-(1-(1,2,3-triazolyl)-4-(4-chlorophenyl)butane(Reference Example 62) 50 mg (0.2 mmol),2-methyl-2-(4-chlorophenoxy)-propanoic acid (44 mg, 0.2 mmol),disiopropylethylamine (0.102 mL, 0.6 mmol), and PYBOP (117 mg, 0.22mmol) in 2 mL CH₂Cl₂ was stirred overnight at room temperature. Themixture was then purified by TLC eluted with ether 3 times. UV activeareas were scraped and stirred in EtOAc containing 5% MeOH. The solidwas filtered and washed with EtOAc. The filtrate was concentrated. Thefaster moving band gave diastereomer A of the title compound as oil. ¹HNMR (400 MHz, CDCl₃): δ 1.26(d, 3H), 1.47 (s, 3H), 1.49 (s, 3H),3.185-3.232 (m, 1H), 3.404-3.466 (m, 1H), 4.44-4.49 (m, 1H), 4.941-4.992(m, 1H), 6.796-7.256 (d's, 8H), 7.215 (s, 1H), 7.622 (s, 1H). MS: m/e447.1; retention time 3.5 min.

The slower moving band gave Diastereomer B of the title compound as oil.¹H NMR (400 MHz, CDCl₃): δ 1.068(d, 3H), 1.527 (s, 3H), 1.58 (s, 3H),3.14-3.256 (m, 2H), 4.54-4.586 (m, 1H), 4.658-4.710 (m, 1H), 6.779-7.263(d's, 8H), 7.167 (s, 1H), 7.597 (s, 1H). MS: m/e 447.1; retention time3.5 min

EXAMPLE 310

N-(2-(1-(1,2,4-triazolyl))-3-(4-chlorophenyl)-1-methylpropyl)-2-(2-pyridyloxy)-2-methylpropanamide

The individual diastereomers were independently prepared from the aminesfrom Reference Example 63 (which were derived from the reduction of thetwo separated diastereomeric azides) and 2-pyridyloxy-2-methylpropanoicacid instead of 2-methyl-2-(4-chlorophenoxy)-propanoic acid according tothe procedures described in Example 309.

The Diastereomer A of the title compound from the faster moving azide:LC-MS: m/e 447.1; retention time 2.9 min. ¹H NMR (400 MHz, CDCl₃): δ1.095(d, 3H), 1.659 (s, 3H), 1.668 (s, 3H), 3.14-3.186 (m, 1H),3.256-3.318 (m, 1H), 4.376-4.427 (m, 1H), 4.554-4.603 (m, 1H), 6.22 (d,1H), 6.763 (d, 1H), 6.858 (d, 2H), 6.908-6.939 (m, 1H), 7.161 (d, 2H),7.50 (s, 1H), 7.605-7.649 (m, 1H), 7.911 (s, 1H).

The title diastereomeric amide derived from the slower moving azide onsilica gel: LC-MS: m/e 447.1; retention time 3.0 min. ¹H NMR (400 MHz,CDCl₃): δ 0.881 (d, 3H), 1.719 (s, 3H), 1.818 (s, 3H), 2.94-3.025 (m,2H), 4.225-4.27 (m, 1H), 4.551-4.60 (m, 1H), 6.694 (d, 2H), 6.822-6.852(m, 1H), 6.895 (d, 1H), 7.151 (d, 2H), 7.553 (s, 1H), 7.604-7.648 (m,1H), 7.856 (s, 1H), 8.042-8.058 (m, 1H).

Examples 311-323 (Table 12) were prepared fromN-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]amine, hydrochloride(Reference Example 11) orN-[3-(5-chloro-2-pyridyl)-2(S)-phenyl-1(S)-methylpropyl]amine,hydrochloride (Reference Example 66) and the appropriate carboxylic acidfollowing the procedures described in Examples 62-63 (via an acylchloride intermediate) or Example 200 (with a coupling reagent).

TABLE 12 retention HPLC-mass Ex. time spectrum No. Name Structure (min)m/e 311. N-[3-(5-chloro-2- pyridyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(5- chloro-2-pyridyloxy)-2- methylpropanamide

3.8 458 312. N-[3-(4-chlorophenyl)- 2(S)-phenyl-1(S)-methylpropyl]-2-(3- trifluoromethylphenyloxy)- 2-methylpropanamide

4.6 490 313. N-[3-(4-chlorophenyl)- 2(S)-phenyl-1(S)-methylpropyl]-2-(6- chloro-2-pyridyloxy)-2- methylpropanamide

4.2 457 314. N-[3-(4-chlorophenyl)- 2(S)-phenyl-1(S)-methylpropyl]-2-(4- cyanophenyloxy)-2- methylpropanamide

4.1 447 315. N-[3-(4-chlorophenyl)- 2(S)-phenyl-1(S)-methylpropyl]-2-(3- cyanophenyloxy)-2- methylpropanamide

4.1 447 316. N-[3-(5-chloro-2- pyridyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.7 492 317. N-[3-(4-chlorophenyl)- 2(S)-phenyl-1(S)-methylpropyl]-2-(5- chloro-2-pyrimidyloxy)- 2-methylpropanamide

3.9 458 318. N-[3-(4-chlorophenyl)- 2(S)-phenyl-1(S)-methylpropyl]-2-(2- pyrimidyloxy)-2- methylpropanamide

3.6 424 319. N-[3-(4-chlorophenyl)- 2(S)-phenyl-1(S)-methylpropyl]-2-(4- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.3 491 320. N-[3-(4-chlorophenyl)- 2(S)-phenyl-1(S)-methylpropyl]-2-(4- trifluoromethyl-2- pyrimidyloxy)-2-methylpropanamide

3.9 492 321. N-[3-(4-chlorophenyl)- 2(S)-phenyl-1(S)-methylpropyl]-2-(4- pyrimidyloxy)-2- methylpropanamide

3.2 424 322. N-[3-(4-chlorophenyl)- 2(S)-phenyl-1(S)- methylpropyl]-2(R)-(4- trifluoromethyl-2- pyridyloxy)propanamide

3.8 477 323. N-[3-(4-chlorophenyl)- 2(S)-phenyl-1(S)-methylpropyl]-2-(4- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

4.1 492

Examples 324-363 (Table 13) were prepared from the appropriate amine andacid of Reference Examples following the procedures described inExamples 62-63 (via an acyl chloride intermediate) or Example 200 (witha coupling reagent).

TABLE 13 retention HPLC-mass Ex. time spectrum Diastereomer No. NameStructure (min) m/e α and/or β 324. N-[3-(4-Chlorophenyl)-2-(3-fluorophenyl)-1- methylpropyl]-2-(5- chloro-2-pyridyloxy)-2-methylpropanamide

4.3 475 α 325. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.2 509 α 326. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

4.1 510 α 327. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(4- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.3 509 α 328. N-[2-(3-Bromo-5-fluoro- phenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

4.3 571 α 329. N-[2-(3-Bromo-5-fluoro- phenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

4.4 587 α 330. N-[2-(3-Bromo-5-fluoro- phenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

4.1 572 α 331. N-[2-(3-Bromo-5-fluoro- phenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

4.3 588 α 332. N-[2-(3-Chlorophenyl)- 3-(4-chlorophenyl)-1-methylpropyl]-2-(5- chloro-2-pyridyloxy)- 2-methylpropanamide

4.4 491 α 333. N-[2-(3-Chlorophenyl)- 3-(5-chloro-2-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.0 526 α 334. N-[2-(3-Chlorophenyl)- 3-(4-chlorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.4 525 α 335. N-[2-(3-Bromophenyl)- 3-(4-chlorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.4 569 α 336. N-[2-(3-Bromophenyl)- 3-(5-chloro-2-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.9 570 α 337. N-[3-(4-Chlorophenyl)- 2-(3-trifluoromethyl-phenyl)-1-methylpropyl]- 2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

4.4 559 α 338. N-[3-(4-Chlorophenyl)- 2-(3-methylphenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.4 505 α 339. N-[3-(4-Chlorophenyl)- 2-(3-cyanophenyl)-1-methylpropyl]-2-(5- chloro-2-pyridyloxy)- 2-methylpropanamide

4.0 482 α 340. N-[3-(4-Chlorophenyl)- 2-(3-cyanophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.1 516 α 341. N-[3-(5-Chloro-2- pyridyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.6 517 α 342. N-[3-(4-Chlorophenyl)- 2-(3-cyanophenyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

4.0 517 α 343. N-[3-(4-Chlorophenyl)- 2-(2-pyridyl)-1-methyl-propyl]-2-(5-trifluoro- methyl-2-pyridyloxy)-2- methylpropanamide

2.8 492 α 344. N-[3-(4-Chlorophenyl)- 2-(3-pyridyl)-1-methyl-propyl]-2-(5-trifluoro- methyl-2-pyridyloxy)-2- methylpropanamide

2.7 492 α 345. N-[3-(4-Chlorophenyl)- 2-(5-fluoro-3-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

3.6 510 α 346. N-[3-(4-Chlorophenyl)- 2-(5-fluoro-3-pyridyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.4 511 α 347. N-[3-(4-Chlorophenyl)- 2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

3.9 526 α 348. N-[3-(4-Chlorophenyl)- 2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(4- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

3.9 526 α 349. N-[3-(4-Chlorophenyl)- 2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(4- trifluoromethyl-2- pyrimidyloxy)-2-methylpropanamide

3.5 527 α 350. N-[3-(4-Chlorophenyl)- 2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.6 527 α 351. N-[3-(4-Chlorophenyl)- 2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyridyloxy)-2- methylpropanamide

3.8 510 α 352. N-[2-(5-Chloro-3- pyridyl)-3-cyclobutyl-1-methylpropyl]-2-(6- trifluoromethyl-4- pyridyloxy)-2-methylpropanamide

4.0 470 α/β 6:1 353. N-[2-(5-Chloro-3- pyridyl)-3-cyclobutyl-5-methyl-2-hexyl]-2- (6-trifluoromethyl-4- pyridyloxy)-2-methylpropanamide

3.9 458 α/β 6:1 354. N-[3-(4-Chlorophenyl)- 2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

3.7 517 α 355. N-[3-(4-Chlorophenyl)- 2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.6 518 α 356. N-[3-(4-Chlorophenyl)- 2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(4- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

3.9 517 α 357. N-[2-(5-Bromo-3- pyridyl)-3-(4-chloro-phenyl)-1-methylpropyl]- 2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

4.0 570 α 358. N-[2-(5-Bromo-3- pyridyl)-3-(4-fluoro-phenyl)-1-methylpropyl]- 2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.8 554 α 359. N-[2-(5-Bromo-3- pyridyl)-3-(4-fluoro-phenyl)-1-methylpropyl]- 2-(4-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.9 554 α 360. N-[2-(5-Bromo-3- pyridyl)-3-(4-chloro-phenyl)-1-methylpropyl]- 2-(4-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

4.0 570 α 361. N-[2-(5-Bromo-3- pyridyl)-3-(4-fluoro-phenyl)-1-methylpropyl]- 2-(6-trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.7 555 α 362. N-[2-(5-Bromo-3- pyridyl)-3-(4-chloro-phenyl)-1-methylpropyl]- 2-(6-trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.9 571 α 363. N-[3-(4-Chlorophenyl)- 2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

2.8 506 α

Examples 364-436 (Table 14) were isolated as single enantiomers from thecorresponding racemic material (Table 13) following the proceduresdescribed in Examples 149-150 with appropriate modifications of (1) theeluent composition (4-15% ethanol/hexane), (2) flow rate (6-9 mL/min)and (3) injection volume (200 to 2000 μL).

TABLE 14 Enantiomeric compounds isolated according to the methodsdescribed in Examples 149-150. retention HPLC-mass Ex. time spectrumEnantiomer No. Name Structure (min) m/e A or B 364.N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1- methylpropyl]-2-(5-chloro-2-pyridyloxy)-2- methylpropanamide

4.4 475 A 365. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(5- chloro-2-pyridyloxy)-2- methylpropanamide

4.4 475 B 366. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.2 509 A 367. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.2 509 B 368. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

4.1 510 A 369. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

4.1 510 B 370. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(4- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.3 509 A 371. N-[3-(4-Chlorophenyl)- 2-(3-fluorophenyl)-1-methylpropyl]-2-(4- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.3 509 B 372. N-[2-(3-Chlorophenyl)- 3-(4-chlorophenyl)-1-methylpropyl]-2-(5- chloro-2-pyridyloxy)-2- methylpropanamide

4.5 491 A 373. N-[2-(3-Chlorophenyl)- 3-(4-chlorophenyl)-1-methylpropyl]-2-(5- chloro-2-pyridyloxy)-2- methylpropanamide

4.5 491 B 374. N-[2-(3-Chlorophenyl)- 3-(5-chloro-2-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.9 526 B 375. N-[2-(3-Chlorophenyl)- 3-(5-chloro-2-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.9 526 A 376. N-[2-(3-Chlorophenyl)- 3-(4-chlorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.4 525 A 377. N-[2-(3-Chlorophenyl)- 3-(4-chlorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.4 525 B 378. N-[2-(3-Bromophenyl)- 3-(4-chlorophenyl)-1-methylpropyl]-2-(5- chloro-2-pyridyloxy)-2- methylpropanamide

4.3 579 A 379. N-[2-(3-Bromophenyl)- 3-(4-chlorophenyl)-1-methylpropyl]-2-(5- chloro-2-pyridyloxy)-2- methylpropanamide

4.3 579 B 380. N-[2-(3-Bromophenyl)- 3-(5-chloro-2-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.9 570 A 381. N-[2-(3-Bromophenyl)- 3-(5-chloro-2-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.9 570 B 382. N-[3-(4-chlorophenyl)- 2-(3-trifluoromethyl-phenyl)-1-methylpropyl]- 2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

4.4 559 A 383. N-[3-(4-chlorophenyl)- 2-(3-trifluoromethylphenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

4.4 559 B 384. N-[3-(4-chlorophenyl)- 2-(3-methylphenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.4 505 A 385. N-[3-(4-chlorophenyl)- 2-(3-methylphenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

4.4 505 B 386. N-[3-(4-chlorophenyl)- 2-(3-cyanophenyl)-1-methylpropyl]-2-(5- chloro-2-pyridyloxy)-2- methylpropanamide

4.2 482 A 387. N-[3-(4-chlorophenyl)- 2-(3-cyanophenyl)-1-methylpropyl]-2-(5- chloro-2-pyridyloxy)-2- methylpropanamide

4.2 482 B 388. N-[3-(4-chlorophenyl)- 2-(3-cyanophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

3.9 516 A 389. N-[3-(4-chlorophenyl)- 2-(3-cyanophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

3.9 516 B 390. N-[3-(4-Chlorophenyl)- 2-(2-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

2.8 492 A 391. N-[3-(4-Chlorophenyl)- 2-(2-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

2.8 492 B 392. N-[3-(4-Chlorophenyl)- 2-(3-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

2.7 492 B 393. N-[3-(4-Chlorophenyl)- 2-(5-fluoro-3-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

3.6 510 A 394. N-[3-(4-Chlorophenyl)- 2-(5-fluoro-3-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

3.6 510 B 395. N-[3-(4-Chlorophenyl)- 2-(5-fluoro-3-pyridyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.4 511 A 396. N-[3-(4-Chlorophenyl)- 2-(5-fluoro-3-pyridyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.4 511 B 397. N-[3-(4-Chlorophenyl)- 2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.8 526 A 398. N-[3-(4-Chlorophenyl)- 2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.8 526 B 399. N-[3-(4-Chlorophenyl)- 2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(4- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.9 526 A 400. N-[3-(4-Chlorophenyl)- 2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(4- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.9 526 B 401. N-[3-(4-Chlorophenyl)- 2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(4- trifluoromethyl-2- pyrimidyloxy)-2-methylpropanamide

3.5 527 A 402. N-[3-(4-Chlorophenyl)- 2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(4- trifluoromethyl-2- pyrimidyloxy)-2-methylpropanamide

3.5 527 B 403. N-[3-(4-Chlorophenyl)- 2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.6 527 A 404. N-[3-(4-Chlorophenyl)- 2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.6 527 B 405. N-[2-(5-chloro-3- pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-4- pyridyloxy)-2-methylpropanamide

3.8 510 A 406. N-[2-(5-chloro-3- pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-4- pyridyloxy)-2-methylpropanamide

3.8 510 B 407. N-[2-(5-chloro-3- pyridyl)-3-cyclobutyl-1-methylpropyl]-2-(5- trifluoromethyl-4- pyridyloxy)-2- methylpropanamide

4.0 470 A 408. N-[2-(5-chloro-3- pyridyl)-3-cyclobutyl-1-methylpropyl]-2-(5- trifluoromethyl-4- pyridyloxy)-2- methylpropanamide

4.0 470 B 409. N-[2-(5-chloro-3- pyridyl)-3-cyclobutyl-1-methylpropyl]-2-(5- trifluoromethyl-4- pyridyloxy)-2- methylpropanamide

4.0 470 C 410. N-[2-(5-chloro-3- pyridyl)-3-cyclobutyl-1-methylpropyl]-2-(5- trifluoromethyl-4- pyridyloxy)-2- methylpropanamide

4.0 470 D 411. N-[2-(5-chloro-3- pyridyl)-1,4-dimethyl-pentyl]-2-(5-trifluoro- methyl-4-pyridyloxy)-2- methylpropanamide

3.9 458 A 412. N-[2-(5-chloro-3- pyridyl)-1,4-dimethyl-pentyl]-2-(5-trifluoro- methyl-4-pyridyloxy)-2- methylpropanamide

3.9 458 B 413. N-[2-(5-chloro-3- pyridyl)-1,4-dimethyl-pentyl]-2-(5-trifluoro- methyl-4-pyridyloxy)-2- methylpropanamide

3.9 458 C 414. N-[2-(5-chloro-3- pyridyl)-1,4-dimethyl-pentyl]-2-(5-trifluoro- methyl-4-pyridyloxy)-2- methylpropanamide

3.9 458 D 415. N-[3-(4-Chlorophenyl)- 2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

3.7 517 A 416. N-[3-(4-Chlorophenyl)- 2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

3.7 517 B 417. N-[3-(4-Chlorophenyl)- 2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.6 518 A 418. N-[3-(4-Chlorophenyl)- 2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.6 518 B 419. N-[2-(5-cyano-3-pyridyl)- 3-(3,4-difluorophenyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.7 519 A 420. N-[2-(5-cyano-3-pyridyl)- 3-(3,4-difluorophenyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.7 519 B 421. N-[3-(3-Chlorophenyl)- 2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

3.8 517 A 422. N-[3-(3-Chlorophenyl)- 2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2- methylpropanamide

3.8 517 B 423. N-[2-(5-cyano-3- pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.7 501 A 424. N-[2-(5-cyano-3- pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.7 501 B 425. N-[2-(5-Bromo-3- pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

4.0 570 A 426. N-[2-(5-Bromo-3- pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

4.0 570 B 427. N-[2-(5-Bromo-3- pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.8 554 A 428. N-[2-(5-Bromo-3- pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

3.8 554 B 429. N-[2-(5-Bromo-3- pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.7 555 A 430. N-[2-(5-Bromo-3- pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.7 555 B 431. N-[2-(5-Bromo-3- pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.8 571 A 432. N-[2-(5-Bromo-3- pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(6- trifluoromethyl-4- pyrimidyloxy)-2-methylpropanamide

3.8 571 B 433. N-[3-(4-Chlorophenyl)- 2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

2.8 506 A 434. N-[3-(4-Chlorophenyl)- 2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5- trifluoromethyl-2- pyridyloxy)-2-methylpropanamide

2.8 506 B 435. N-[2-(3-Bromophenyl)- 3-(4-chlorophenyl)-1-methylpropyl]-2-(5- chloro-2-pyridyloxy)-2- methylpropanamide

4.5 535 A 436. N-[2-(3-Bromophenyl)- 3-(4-chlorophenyl)-1-methylpropyl]-2-(5- chloro-2-pyridyloxy)-2- methylpropanamide

4.5 535 B

EXAMPLE 437

N-[3-(4-Chlorophenyl)-2-(3-cyano-5-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Diastereomer α and Enantiomer A and B)

A mixture ofN-[2-(3-bromo-5-fluorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Example 330, 92 mg, 0.16 mmol), sodium cyanide (12 mg, 0.24 mmol),18-crown-6 (63 mg, 0.24 mmol) and tetrakis(triphenylphosphine)palladium(92 mg, 0.08 mmol) in 2 mL dioxane was heated under nitrogen at 100° C.for 14 h. After cooling to room temperature, the resulting mixture waspartitioned between water (50 mL) and EtOAc (50 mL). The organic layerwas separated, washed with water, dried over anhydrous sodium sulfate,filtered and concentrated, and the residue was purified by flash columnchromatography on silica gel eluting with 30% EtOAc in hexane to affordthe title compound as a racemic mixture. ¹H NMR (500 MHz, CD₃OD): δ 8.26(br s, 1H), 7.96 (d, 1H), 7.93 (dd, 1H), 7.30 (br d, 1H), 7.22 (s, 1H),7.15 (br d, 1H), 7.06 (d, 2H), 7.05 (m, 1H), 6.74 (d, 2H), 4.24 (m, 1H),3.05 (dd, 1H), 2.91 (m, 1H), 2.63 (dd, 1H), 1.74 (s, 3H), 1.72 (s, 3H),0.83 (d, 3H). LC-MS: m/e 534 (M+H)⁺ (4.2 min).

The racemic mixture obtained above was separated into Enantiomer A andEnantiomer B by preparative HPLC eluting on a Chiralpak AD column (2cm×25 cm), with 8% ethanol in hexane (flow rate 9 mL/min, 500 μL perinjection).

Faster eluting enantiomer (Enantiomer A): Analytical HPLC: retentiontime=8.2 min (Chiralpak AD column, flow rate=0.75 mL/min, 8%ethanol/hexane). LC-MS: m/e 534 (M+H)⁺ (4.2 min).

Slower eluting enantiomer (Enantiomer B): Analytical HPLC: retentiontime=11.0 min (Chiralpak AD column, flow rate=0.75 mL/min, 8%ethanol/hexane). LC-MS: m/e 534 (M+H)⁺ (4.2 min).

EXAMPLE 438

N-[2-(3-Cyano-5-fluorophenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Diastereomer α and Enantiomer A and B)

The title compounds were prepared fromN-[2-(3-bromo-5-fluorophenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Example 329) following the procedure described in Example 437. LC-MS:m/e 518 (M+H)⁺ (4.1 min).

Faster eluting enantiomer (Enantiomer A): Analytical HPLC: retentiontime=8.2 min (Chiralpak AD column, flow rate=0.75 mL/min, 8%ethanol/hexane). LC-MS: m/e 518 (M+H)⁺ (4.1 min).

Slower eluting enantiomer (Enantiomer B): Analytical HPLC: retentiontime=11.2 min (Chiralpak AD column, flow rate=0.75 mL/min, 8%ethanol/hexane). LC-MS: m/e 518 (M+H)⁺ (4.1 min).

EXAMPLE 439

N-[2-(3-Cyano-5-fluorophenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide(Diastereomer α)

The title compound was prepared fromN-[2-(3-bromo-5-fluorophenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide(Example 331) following the procedure described in Example 437. LC-MS:m/e 519 (M+H)⁺ (3.8 min).

EXAMPLE 440

N-[3-(4-Chlorophenyl)-2-(3-cyano-5-fluorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide(Diastereomer α)

The title compound was prepared fromN-[2-(3-bromo-5-fluorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide(Example 332) following the procedure described in Example 4370. LC-MS:m/e 535 (M+H)⁺ (4.1 min).

EXAMPLE 441

N-[3-(5-Chloro-2-pyridyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Enantiomer A and B)

The title compounds were prepared fromN-[2-(3-bromophenyl)-3-(5-chloro-2-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Example 382) following the procedure described in Example 437.

Faster eluting enantiomer (Enantiomer A): Analytical HPLC: retentiontime=8.9 min (Chiralpak AD column, flow rate=0.75 mL/min, 10%ethanol/hexane). LC-MS: m/e 517 (M+H)⁺ (3.6 min).

Slower eluting enantiomer (Enantiomer B): Analytical HPLC: retentiontime=11.1 min (Chiralpak AD column, flow rate=0.75 mL/min, 10%ethanol/hexane). LC-MS: m/e 517 (M+H)⁺ (3.6 min).

EXAMPLE 442

N-[2-(5-Chloro-3-pyridyl)-3-(4-chloro-3-iodophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Enantiomer B)

The procedure of Barluenga (J Org Chem 1990, 55, 3104) was used. Thus,to a solution ofN-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Example 398, 22 mg, 0.041 mmol) and bis(pyridine)iodoniumtetrafluoroborate (30 mg, 0.082 mmol) in 0.3 mL anhydrous CH₂Cl₂ wasadded triflic acid (18 μL, 0.20 mmol). After stirring at roomtemperature for 50 min, the reaction mixture was poured into a mixtureof ice (20 g) and sodium bisulfite (1 g) and was extracted with EtOAc.The organic extracts were dried over anhydrous sodium sulfate, filteredand concentrated to dryness to give the crude product, which waspurified by preparative HPLC eluting on a reverse-phase HPLC column with75 to 100% water in acetonitrile (containing 0.1% trifluoroacetic acid)to give the title compound. ¹H NMR (500 MHz, CD₃OD): δ 8.43 (d, 1H),8.32 (s, 1H), 8.10 (s, 1H), 8.04 (d, 1H), 7.99 (dd, 1H), 7.82 (m, 1H),7.36 d, 1H), 7.22 (d, 1H), 7.08 (d, 1H), 6.78 (dd, 1H), 4.29 (m, 1H),3.03 (dd, 1H), 2.94 (m, 1H), 2.64 (dd, 1H), 1.78 (s, 3H), 1.75 (s, 3H),0.88 (d, 3H). LC-MS: m/e 652 (M+H)⁺ (4.1 min).

EXAMPLE 443

N-[3-(4-Chloro-3-iodophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Enantiomer B)

The title compound was prepared fromN-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide (Enantiomer B) (Example 389) following the proceduredescribed in Example 442. ¹H NMR (500 MHz, CD₃OD): δ 8.31 (s, 1H), 8.02(d, 1H), 7.98 (dd, 1H), 7.54 (d, 1H), 7.5-7.4 (m, 2H), 7.35 (d, 1H),7.27 (d, 1H), 7.17 (d, 1H), 7.08 (d, 1H), 6.70 (dd, 1H), 4.27 (m, 1H),2.98 (dd, 1H), 2.84 (m, 1H), 2.61 (dd, 1H), 1.78 (s, 3H), 1.75 (s, 3H),0.83 (d, 3H). LC-MS: m/e 642 (M+H)⁺ (4.2 min).

Examples 444-451 (Table 15) were isolated as diastereomers as indicated(Isomer A or B) on silica gel chromatography columns. The singleenantiomers noted were separated on the chiral AD column noted above.

TABLE 15 HPLC- retention mass Ex. time spectrum Diastereomer No. NameStructure (min) m/e A or B 444. N-(3-(4- chlorophenyl)-2-benzisoxazol-3-yl)-1- methyl)propyl-2-(5- chloro-2-oxypyridine- 2-yl)-2-methylpropanamide

4.1, 4.3 498.1 A and B 445. N-(3-(4- chlorophenyl)-2-(benzisoxazol-3-yl)- 1-methyl)propyl-2- (3,5- dichlorophenoxy)-2-methylpropanamide

4.7, 4.8 532.8 A and B 446. N-(3-(4- chlorophenyl)-2-(benzisoxazol-3-yl)- 1-methyl)propyl-2-(5- trifluoromethyl-2-oxypyridine-2-yl)2- methylpropanamide

4.2 532.1 B 447. N-(3-(4- chlorophenyl)-2-(7- azaindol-N-yl)-1-methyl)propyl-2-(5- trifluoromethyl-2- oxypyridine-2-yl)-2-methylpropanamide

3.89 532.1 B 448. N-(3-(4- chlorophenyl)-2-(N- methyl-N- phenyl)amino-1-methyl)propyl-2-(5- trifluoromethyl-2- oxypyridine-2-yl)-2-methylpropanamide

4.40 521 Single enantiomer derived from Isomer B 449. N-(3-(4-chlorophenyl)-2- (indol-N-yl)-1- methyl)propyl-2-(5- trifluoromethyl-2-oxypyridine-2-yl)-2- methylpropanamide

  4.32^(b,c) 531 Single enantiomer derived from Isomer B 450. N-(3-(4-chlorophenyl)-2- (indolin-N-yl)-1- methyl)propyl-2(4- trifluoromethyl-2-oxypyridine-2-yl)-2- methylpropanamide

 4.32^(b) 531 B 451. N-(3-(4- chlorophenyl)-2- (indolin-N-yl)-1-methyl)propyl-2(5- trifluoromethyl-2- oxypyridine-2-yl)-2-methylpropanamide

 4.40^(b) 532 B

EXAMPLE 452

2-Methyl-N-[1-methyl-3-(4-methylphenyl)-2-phenylpropyl]-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide

To a solution of2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoic acid(Reference example 55, 250 mg, 1.04 mmol) and4-(4-methylphenyl)-3-phenylbutan-2-amine (Reference example 102, 260 mg,1.04 mmol, mixture of 4 isomers) in CH₂Cl₂ (5.5 mL) at RT was addeddiisopropylethylamine (272 μl, 1.56 mmol) followed by PyBOP (649 mg,1.25 mmol) and the reaction mixture stirred overnight. The reaction waspurified by loading the reaction mixture directly onto a silica gelcolumn and eluting from 0-30% EtOAc/hexane to give the title compound asa mixture of 4 isomers. The diastereomers were separated by HPLC on aZORBAX RxSi column eluting 97% hexane: 3% ethanol at 20 mL/min withretention times of:

-   less polar diastereomer eluted at 4.73 minutes; more polar    diasteromer eluted at 5.87 minutes. The more polar diastereomer was    additionally separated into enantiomers on a ChiralPak AD column    eluting with 95% hexane: 5% ethanol at 8 mL/min with retention times    of:-   less polar enantiomer eluted at 6.84 minutes; more polar    diastereomer eluted at 8.36 minutes.

Less polar diastereomer: ¹H NMR (500 MHz, CDCl3): δ 8.44 (s, 1H), 7.86(dd, J=8.6, 2.5 Hz, 1H), 7.19 (t, J=3.2 Hz, 3H), 7.00 (dd, J=21.3, 8.0Hz, 4H), 6.91 (m, 2H), 6.83 (d, J=8.7 Hz, 1H), 5.70 (d, J=9.4 Hz, 1H),4.43 (m, 1H), 3.02 (dd, J=13.3, 6.7 Hz, 1H), 2.84 (dt, J=7.3, 4.3 Hz,1H), 2.84 (dd, J=13.2, 7.7 Hz, 1H), 2.29 (s, 3H), 1.69 (s, 3H), 1.66 (s,3H), 1.03 (d, J=6.8 Hz, 3H). LC-MS: m/e 471 (M+H)⁺ (4.22 min)

More polar diastereomer: ¹H NMR (500 MHz, CDCl₃): δ 8.40 (s, 1H), 7.83(dd, J=8.7, 2.6 Hz, 1H), 7.21 (m, 3H), 7.00 (dd, J=30.4, 6.2 Hz, 4H),6.82 (t, J=9.2 Hz, 3H), 5.84 (d, J=9.2 Hz, 1H), 4.36 (ddt, J=9.1, 6.7,6.6 Hz, 1H), 3.06 (dd, J=12.8, 4.1 Hz, 1H), 2.88 (m, 1H), 2.26 (s, 3H),1.78 (s, 3H), 1.73 (s, 3H), 0.92 (d, J=6.6 Hz, 3H). LC-MS: m/e 471(M+H)⁺ (4.17 min).

EXAMPLE 453

N-[3-(4-Methoxyphenyl)-1-methyl-2-phenylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide

Prepared as in Example 452 using4-(4-methoxyphenyl)-3-phenylbutan-2-amine (Reference example 103) as theamine component to give the title compound as a mixture of 4 isomers.The diastereomers were separated by HPLC on a ZORBAX RxSi column eluting97% hexane: 3% ethanol at 20 mL/min with retention times of: less polardiastereomer eluted at 6.12 minutes; more polar diasteromer eluted at7.74 minutes. The more polar diastereomer was additionally separatedinto enantiomers on a ChiralPak AD column eluting with 90% hexane: 10%ethanol at 8 mL/min with retention times of: less polar enantiomereluted at 6.19 minutes; more polar diastereomer eluted at 7.22 minutes.

Less polar diastereomer: ¹H NMR (500 MHz, CDCl₃): δ 8.44 (s, 1H), 7.86(dd, J=8.7, 2.5 Hz, 1H),7.19 (t, J=2.8 Hz, 3H), 7.01 (d, J=8.5 Hz, 2H),6.90 (m, 2H), 6.83 (d, J=8.7 Hz, 1H), 6.77 (d, J=8.5 Hz), 5.70 (d, J=9.6Hz, 1H), 4.42 (m, 1H), 3.77 (s, 3H), 2.99 (dd, J=13.5, 6.6 Hz, 1H), 2.89(m, 1H), 2.80 (dd, J=13.3, 7.6 Hz, 1H) 1.69 (s, 3H), 1.67 (s, 3H), 1.03(d, J=6.6 Hz, 3H). LC-MS: m/e 471 (M+H)⁺ (3.96 min)

More polar diastereomer: ¹H NMR (500 MHz, CDCl₃): δ 8.41 (s, 1H), 7.83(dd, J=8.7, 2.6 Hz, 1H), 7.21 (m, 3H), 7.01 (m, 2H), 6.82 (m, 3H), 6.70(m, 2H) 5.84 (d, J=9.2 Hz, 1H), 4.36 (ddt, J=9.1, 6.7, 6.6 Hz, 1H), 3.75(s, 3H), 3.06 (dd, J=13.3, 4.6 Hz, 1H), 2.85 (m, 2H), 1.78 (s, 3H), 1.73(s, 3H), 0.92 (d, J=6.8 Hz, 3H). LC-MS: m/e 471 (M+H)⁺ (4.02 min).

EXAMPLE 454

N-[3-(4-Fluorophenyl)-1-methyl-2-phenylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide

Prepared as in Example 452 using4-(4-fluorophenyl)-3-phenylbutan-2-amine (Reference example 105) as theamine component to give the title compound as a mixture of 4 isomers.The diastereomers were separated by HPLC on a ZORBAX RxSi column eluting96% hexane: 4% ethanol at 20 mL/min with retention times of: less polardiastereomer was not isolated, very little present; more polardiasteromer eluted at 6.65 minutes. The more polar diastereomer wasadditionally separated into enantiomers on a ChiralPak AD column elutingwith 92% hexane: 8% ethanol at 8 mL/min with retention times of: lesspolar enantiomer eluted at 6.06 minutes; more polar diastereomer elutedat 7.02 minutes. More polar diastereomer: ¹H NMR (500 MHz, CDCl₃): δ8.42 (s, 1H), 7.85 (dd, J=8.7, 2.5 Hz, 1H), 7.22 (m, 3H), 7.01 (m, 2H),7.00 (m, 2H), 6.84 (m, 5H) 5.85 (d, J=9.1 Hz, 1H), 4.39 (ddt, J=9.1,6.7, 6.6 Hz, 1H), 2.89 (dd, J=13.7, 10.3 Hz, 1H), 2.80 (ddd, J=10.3,7.8, 4.8 Hz, 1H), 1.80 (s, 3H), 1.75 (s, 3H), 0.93 (d, J=6.7 Hz, 3H).LC-MS: m/e 475 (M+H)⁺ (4.11 min).

EXAMPLE 455

N-[3-(4-Cyanophenyl)-1-methyl-2-phenylpropyl]-2-methyl-2{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide

Prepared as in Reference example 452 using4-(4-cyanophenyl)-3-phenylbutan-2-amine (Reference example 17) as theamine component to give the title compound as a mixture of 4 isomers.The diastereomers were separated by HPLC on a Zorbax RxSi column eluting90% hexane: 10% ethanol at 20 mL/min with retention times of: less polardiastereomer was not isolated, very little present; more polardiasteromer eluted at 6.44 minutes. The more polar diastereomer wasadditionally separated into enantiomers on a ChiralPak AD column elutingwith 92% hexane: 8% ethanol at 8 mL/min with retention times of: lesspolar enantiomer eluted at 8.83 minutes; more polar diastereomer elutedat 10.83 minutes.

More polar diastereomer: ¹H NMR (500 MHz, CDCl₃): δ 8.42 (s, 1H), 7.86(dd, J=8.6, 2.2 Hz, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.01 (m, 2H), 7.20 (m,3H), 6.97 (m, 2H), 6.93 (d, J=8.2 Hz, 2H), 6.87 (d, J=8.7 Hz, 1H), 5.85(d, J=9.2 Hz, 1H), 4.38 (dq, J=15.5, 8.4 Hz, 1H), 3.17 (dd, J=13.9, 4.5Hz, 1H), 2.95 (dd, J=13.7, 10.7 Hz, 1H), 2.78 (m, 1H), 1.79 (s, 3H),1.74 (s, 3H), 0.92 (d, J=6.8 Hz, 3H). LC-MS: m/e 482 (M+H)⁺ (4.27 min).

EXAMPLE 456

N-[2-(3-Cyanophenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide

Prepared as in Example 452 only using3-[2-amino-1-(4-fluorobenzyl)propyl]benzonitrile (Reference example 104)as the amine component to give the title compound as a mixture of 4isomers. The diastereomers were separated by HPLC on a Zorbax RxSicolumn eluting 96% hexane: 4% ethanol at 20 mL/min with retention timesof: less polar diastereomer eluted at 11.75 minutes; more polardiasteromer eluted at 15.17 minutes. The more polar diastereomer wasadditionally separated into enantiomers on a ChiralPak AD column elutingwith 92% hexane: 8% ethanol at 8 mL/min with retention times of: lesspolar enantiomer eluted at 9.65 minutes; more polar diastereomer elutedat 11.78 minutes.

Less polar diastereomer: ¹H NMR (500 MHz, CD₃OD): δ 8.29 (s, 1H), 7.93(dd, J=8.7, 2.5 Hz, 1H), 7.50 (m, 1H), 7.42 (m, 1H), 7.27 (m, 2H),6.96-6.78 (m, 5H 5.70 (d, J=9.6 Hz, 1H), 4.33 (m, 1H), 3.18-3.04 (m,2H), 2.7 (dd, J=13.5, 6.6 Hz, 1H), 1.52 (s, 3H), 1.35 (s, 3H), 1.17 (d,J=6.6 Hz, 3H). LC-MS: m/e 500 (M+H)⁺ (4.33 min)

More polar diastereomer: ¹H NMR (500 MHz, CD₃OD): δ 8.28 (s, 1H), 7.95(dd, J=8.7, 2.5 Hz, 1H), 7.50 (d, J=7.5 Hz, 1H), 7.36 (m, 3H), 7.05 (d,J=8.9 Hz, 3H), 6.78 (m, 2H), 6.72 (m, 2H) 4.26 (dq, J=10, 6.6 Hz, 1H),3.04 (dd, J=13.7, 3.4 Hz, 1H), 2.85 (ddt J=11.2, 3.7 Hz, 1H), 2.63 (dd,J=13.7, 11.4 Hz, 1H), 1.77 (s, 3H), 1.74 (s, 3H), 0.81 (d, J=6.8 Hz,3H). LC-MS: m/e 500 (M+H)⁺ (4.25 min).

The compounds of Table 16 were prepared from the appropriate amine andacid of the Reference Examples following the procedures described inExamples 62-63 (via an acyl chloride intermediate) or Examples 195 or200 (with a coupling reagent.)

TABLE 16 HPLC- retention mass Ex. time spectrum No. Name Structure (min)m/e 457. N-(2-(1H-1,2,3- Benzotriazol-1-yl)-3-(4- chlorophenyl)-1-methylpropyl)-2-methyl-2- (5-chloropyridin-2-yl)oxy)-2-methylpropanamide

3.8 498 458. N-(2-(1H-1,2,3- Benzotriazol-1-yl)-3-(4- chlorophenyl)-1-methylpropyl)-2-methyl-2- (5-trifluoropyridin- 2-yl)oxy)-2-methylpropanamide

3.9 532 459. N-(2-(1H-1,2,3- Benzotriazol-1-yl)-3-(4- chlorophenyl)-1-methylpropyl)-2-methyl-2- (4-chlorophenoxy)- 2-methylpropanamide

4.1 497 460. N-(3-(4-chlorophenyl)-1- methyl-2-(1H-indazol-1-yl)propyl)-2-methyl-2-(5- trifluoromethylpyridin-2- yl)oxy)-2-methylpropanamide

4.1 531 461. N-(3-(4-chlorophenyl)-1- methyl-2-(1-methyl-1H-indol-3-yl)propyl)-2- methyl-2-(5-chloropyridin- 2-yl)oxy)-2-methylpropanamide

4.34 510 462. N-(3-(4-chlorophenyl)-1- methyl-2-(1-methyl-1H-indol-3-yl)propyl)-2- methyl-2-(5- trifluoromethylpyridin-2-2-yl)oxy)-2- methylpropanamide

4.4 544 463. N-(3-(4-chlorophenyl)-1- methyl-2-(1-methyl-1H-indol-3-yl)propyl)-2- methyl-2-(4- chlorophenoxy)-2- methylpropanamide

4.6 409 464. N-(3-(4-chlorophenyl)-1- methyl-2-(1-methyl-1H-indol-4-yl)propyl)-2- methyl-2-(5- trifluoromethylpyridin-2- yl)oxy)-2-methylpropanamide

4.29 544 465. N-(3-(4-chlorophenyl)-1- methyl-2-(thiophen-2-yl)propyl)-2-methyl-2-(5- chloropyridin-2-yl)oxy)-2- methylprpoanamide

4.2 463 466. N-(3-(4-chlorophenyl)-1- methyl-2-(thiophen-3-yl)propyl)-2-methyl-2-(5- chloropyridin-2-yl)oxy)-2- methylprpoanamide

4.21 463 467. N-(3-(4-chlorophenyl)-1- methyl-2-(pyrimidin-5-yl)propyl)-2-methyl-2-(5- chloropyridin-2-yl)oxy)-2- methylprpoanamide

3.39 493 468. N-(3-(4-chlorophenyl)-1- methyl-2-(pyradizin-3-yl)propyl)-2-methyl-2-(5- chloropyridin-2-yl)oxy)-2- methylprpoanamide

3.57 493 469. N-(2-(3-cyanophenyl)-3- cyclopropyl-1-methylpropyl)-2-methyl- 2((5- (trifluoromethyl)pyridin-2-yl)oxy)-propanamide

3.96 446 470. N-(2-(3-cyanophenyl)-1,4- dimethylpentyl)-2-methyl- 2((5-(trifluoromethyl)pyridin-2- yl)oxy)-propanamide

4.0 448 471. N-(2-(3-cyanophenyl)-3- cyclobutyl-1-methylpropyl)-2-methyl- 2((5- (trifluoromethyl)pyridin-2-yl)oxy)-propanamide

4.1 460 472. N-(2-(3-cyanophenyl)-3- cyclohexyl-1-methylpropyl)-2-methyl- 2((5- (trifluoromethyl)pyridin-2-yl)oxy)-propanainide

4.3 488 473. N-(2-(3-cyanophenyl)-3- cyclopentyl-1-methylpropyl)-2-methyl- 2((5- (trifluoromethyl)pyridin-2-yl)oxy)-propanamide

4.2 474 474. N-(2-(3-cyanophenyl)-3- ((1- tertbutyloxycarbonyl)-piperidin-4-yl)-1-methyl- propyl)- 2-methyl-2((5-(trifluoromethyl)pyridin-2- yl)oxy)-propanamide

4.1 589

EXAMPLE 475

N-(2-(2,3-Dihydro-1H-indol-1-yl)-1,4-dimethylpentyl)-2-methyl-2((5-(trifluoromethyl)pyridin-2-yl)oxy)-propanamide

To a solution of 65 mg (0.28 mmol)2-(2,3-Dihydro-1-H-indol-1-yl)-1,4-dimethylpentylamine in 1 mL CH₂Cl₂,65 mg (0.26 mmol) acid, 0.045 mL triethylamine and 0.15 g (0.29 mmol)PyBop were added. After stirring for 3 h, the reaction was quenched byadding 1 mL water and the organic layer was removed with a pipet. Thissolution was purified by prep-TLC using 20% EtOAc-hexane to isolate thelower band: ¹H NMR: (500 MHz, CDCl₃): δ 0.79 (d, 3H), 0.88 (d, 3H), 1.08(d, 3H), 1.21 (m, 1H), 1.63 (m, 2H), 1.74 (s, 6H), 3.01 (m, 2H), 3.44(m, 3H), 4.17 (m, 1H), 6.15 (br d, 1H), 6.2-8.5 (m, 7H); LC-MS, Rt=4.37min, m/e=464 and 20 mg of the higher band: ¹H NMR: (500 MHz, CDCl₃): δ0.88 (d, 3H), 0.90 (d, 3H), 1.16 (d, 3H), 1.3 (m, 1H), 1.6 (s, 6H), 1.62(m, 2H), 2.8-3.5 (m, 5H), 4.13 (m, 1H), 5.98 (br d, 1H), 6.3-8.4 (m,7H); LC-MS, Rt=4.53 min, m/e=464.

The following compounds in Table 17 were prepared from the appropriateamine and acid of the Reference Examples following the proceduresdescribed in Examples 62-63 (via an acyl chloride intermediate) orExamples 195 or 200 (with a coupling reagent.)

TABLE 17 HPLC- retention mass Ex. time spectrum No. Name Structure (min)m/e 476. N-(3-Cyclobutyl-2-(3,4- dihydroquinolin-1(2H)-yl)-1-methylpropyl)-2-methyl- 2((5- (trifluoromethyl)pyridin-2-yl)oxy)-propanamide

4.43 490 477. N-(2-(3,4-dihydroquinolin- 1(2H)-yl)-1,4-dimethylpentyl)-2-methyl- 2((5- (trifluoromethyl)pyridin-2-yl)oxy)-propanamide

4.37 478

The compounds in Table 18 were isolated according to the procedure forseparating enantiomers described in Examples 149-150.

TABLE 18 Enantiomeric compounds isolated according to the methodsdescribed in Examples 149-150. HPLC- retention mass Ex. time spectrumEnantiomer No. Name Structure (min) m/e A or B 478.N-(2-(3-cyanophenyl)-1,4- dimethylpentyl)-2-methyl- 2((5-(trifluoromethyl)pyridin-2- yl)oxy)-propanamide

4.0 448 B 479. N-(2-(3-cyanophenyl)-3- cyclobutyl-1-methylpropyl)-2-methyl- 2((5- (trifluoromethyl)pyridin-2-yl)oxy)-propanamide

4.1 460 B 480. N-(2-(3-cyanophenyl)-3- cyclopentyl-1-methylpropyl)-2-methyl- 2((5- (trifluoromethyl)pyridin-2-yl)oxy)-propanamide

4.18 474 B 481. N-(2-(3-cyanophenyl)-3- cyclohexyl-1-methylpropyl)-2-methyl- 2((5- (trifluoromethyl)pyridin-2-yl)oxy)-propanamide

4.29 488 B

EXAMPLE 482

Pyridine N-Oxide ofN-[3-(4-Chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Enantiomer B)

A mixture ofN-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Enantiomer B, Example 416, 0.10 g, 0.19 mmol) and m-chloroperbenzoicacid (77%, 0.15 g, 0.67 mmol) in 2 mL of methylene chloride was stirredat room temperature for 14 h. The reaction mixture was concentrated andthe residue was purified by HPLC eluting on a reverse phase C18 columnwith 30 to 100% acetonitrile in water (contains 0.1% trifluoroaceticacid) to give the title compound (0.10 g). ¹H NMR (500 MHz, CD₃OD): δ8.58 (s, 1H), 8.32 (br s, 1H), 8.17 (s, 1H), 7.99 (br d, 1H), 7.97 (dd,1H), 7.81 (s, 1H), 7.16 (d, 2H), 7.06 (d, 1H), 6.87 (d, 2H), 4.28 (m,1H), 3.11 (dd, 1H), 3.01 (m, 1H), 2.71 (dd, 1H), 1.75 (s, 3H), 1.74 (s,3H), 0.94 (d, 3H). LC-MS: m/e 533 (M+H)⁺ (4.1 min).

EXAMPLE 483

N-[3-(4-chlorophenyl)-2-(3-methylthiophenyl)-1-methylpropyl]-2-methyl-2-(5-trifluoromethylpyridin-2-oxy)-propanamide

The title compound was prepared following the procedure described inExample 200. ¹H NMR (500 MHz, CDCl₃): δ 8.28 (s, 1H), 7.94 (dd, 1H),7.33 (t, 1H), 7.07-7.00 (m, 4H), 6.85 (s, 1H), 6.80 (d, 1H), 6.67 (d,2H), 4.24 (m, 1H), 2.98 (dd, 1H), 2.70 (m, 1H), 2.58 (dd, 1H), 2.36 (s,3H), 1.77 (s, 3H), 1.74 (s, 3H), 0.82 (d, 3H). LC-MS: m/e 537 (M+H)⁺(4.36 min).

EXAMPLE 484

N-[3-(4-chlorophenyl)-2-(3-methylsulfonylphenyl)-1-methylpropyl]-2-methyl-2-(5-trifluoromethylpyridin-2-oxy)propanamide

To a solution ofN-[3-(4-chlorophenyl)-2-(3-methylthiophenyl)-1-methypropyl]-2-methyl-2-(5-trifluoromethylpyridinyl-2-oxy)propanamide(Example 483, 0.20 g, 0.37 mmol) in 40 mL of methylene chloride wasadded m-chloroperbenzoic acid (0.10 g, 0.60 mmol), and the mixture wasstirred at room temperature overnight. The reaction was quenched byaddition of saturated sodium bisulfite (5 mL) and saturated sodiumbicarbonate (5 mL). After stirring at room temperature for 10 min, thereaction mixture was extracted with ether (2×20 mL). The organicextracts were dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness, and the residue was purified by flash columnchromatography eluting with 0 to 100% ethyl acetate in hexane to givethe title compound. ¹H NMR (500 MHz, CDCl₃): δ 8.30 (s, 1H), 7.96 (dd,1H), 7.74 (d, 1H), 7.52 (s, 1H), 7.49 (t, 1H), 7.41 (d, 1H), 7.08-7.00(m, 3H), 6.70 (d, 2H), 4.34 (m, 1H), 3.07 (dd, 1H), 2.98 (s, 3H), 2.95(m, 1H), 2.64 (dd, 1H), 1.78 (s, 3H), 1.75 (s, 3H), 0.85 (d, 3H). LC-MS:m/e 569 (M+H)⁺ (5.21 min).

Examples 485-489 (Table 19) were isolated as single enantiomersfollowing t he procedures described in Example 189 or Examples 149-150from the corresponding racemic material with appropriate modificationsof (1) the eluent composition (4-15% ethanol/hexane), (2) flow rate (6-9mL/min) and (3) injection volume (200 to 2000 μL).

TABLE 19 Enantiomeric compounds isolated according to the methodsdescribed in Examples 485-489. HPLC- retention mass Ex. time spectrumDiastereomer No. Name Structure (min) m/e A or B 485. N-[3-(4-chlorophenyl)-2-(3- methylsulfonylphenyl)- 1-methylpropyl]-2-methyl-2-(5- trifluoromethylpyridin- 2-oxy)propanamide

3.9 568 A 486. N-[3-(4- chlorophenyl)-2-(3- methylsulfonylphenyl)-1-methylpropyl]-2- methyl-2-(5- trifluoromethylpyridin-2-oxy)propanamide

3.9 568 B 487. N-[3-(4- chlorophenyl)-2-(3- cyanophenyl)-1-methylpropyl]-2- methyl-2-(5- methylsulfonylpyridin- 2-oxy)propanamide

3.3 525 B 488. N-[3-(4- chlorophenyl)-2-(3- methylthiophenyl)-1-methylpropyl]-2- methyl-2-(5- trifluoromethylpyridin- 2-oxy)propanamide

4.3 534 A 489. N-[3-(4- chlorophenyl)-2-(3- methylthiophenyl)-1-methylpropyl]-2- methyl-2-(5- trifluoromethylpyridin- 2-oxy)propanamide

4.3 534 B

EXAMPLE 490

Cannabinoid Receptor-1 (CB1) Binding Assay.

Binding affinity determination is based on recombinant human CB1receptor expressed in Chinese Hamster Ovary (CHO) cells (Felder et al,Mol. Pharmacol. 48: 443-450, 1995). Total assay volume is 250 μl (240 μlCB1 receptor membrane solution plus 5 μl test compound solution plus 5μl [3H]CP-55940 solution). Final concentration of [3H]CP-55940 is 0.6nM. Binding buffer contains 50 mM Tris-HCl, pH7.4, 2.5 mM EDTA, 5 mMMgCl₂, 0.5 mg/mL fatty acid free bovine serum albumin and proteaseinhibitors (Cat#P8340, from Sigma). To initiate the binding reaction, 5μl of radioligand solution is added, the mixture is incubated withgentle shaking on a shaker for 1.5 h at 30° C. The binding is terminatedby using 96-well harvester and filtering through GF/C filter presoakedin 0.05% polyethylenimine. The bound radiolabel is quantitated usingscintillation counter. Apparent binding affinities for various compoundsare calculated from IC50 values (DeBlasi et al., Trends Pharmacol Sci10: 227-229, 1989).

The binding assay for CB2 receptor is done similarly with recombinanthuman CB2 receptor expressed in CHO cells.

EXAMPLE 491

Cannabinoid Receptor-1 (CB1) Functional Activity Assay.

The functional activation of CB1 receptor is based on recombinant humanCB1 receptor expressed in CHO cells (Felder et al, Mol. Pharmacol. 48:443-450, 1995). To determine the agonist activity or inverse agonistactivity of any test compound, 50 ul of CB1-CHO cell suspension aremixed with test compound and 70 ul assay buffer containing 0.34 mM3-isobutyl-1-methylxanthine and 5.1 uM of forskolin in 96-well plates.The assay buffer is comprised of Earle's Balanced Salt Solutionsupplemented with 5 mM MgCl₂.1 mM glutamine, 10 mM HEPES, and 1 mg/mLbovine serum albumin. The mixture is incubated at room temperature for30 minutes, and terminated by adding 30 ul/well of 0.5M HCl. The totalintracellular cAMP level is quantitated using the New England NuclearFlashplate and cAMP radioimmunoassay kit.

To determine the antagonist activity of test compound, the reactionmixture also contains 0.5 nM of the agonist CP55940, and the reversal ofthe CP55940 effect is quantitated. Alternatively, a series of doseresponse curves for CP55940 is performed with increasing concentrationof the test compound in each of the dose response curves.

The functional assay for the CB2 receptor is done similarly withrecombinant human CB2 receptor expressed in CHO cells.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the particulardosages as set forth herein above may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated for any ofthe indications for the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

1. A compound of structural fomula I:

or a pharmaceutically acceptable salt thereof, wherein; R¹ is selectedfrom: (1) aryl, and (2) aryl-C₁₋₄alkyl, wherein each alkyl is optionallysubstituted with one to four substituents independently selected fromR^(a), and each aryl is optionally substituted with one to foursubstituents independently selected from R^(b); R² is selected from: (1)aryl, (2) aryl-C₁₋₄alkyl, wherein each alkyl is optionally substitutedwith one to four substituents independently selected from R^(a), andeach aryl is optionally substituted with one to four substituentsindependently selected from R^(b); R³ is selected from: (1) hydrogen,and (2) C₁₋₄alkyl, wherein each alkyl is optionally substituted with oneto four substituents independently selected from R^(a); R⁴ is selectedfrom: (1) hydrogen, and (2) C₁₋₄alkyl, wherein each alkyl is optionallysubstituted with one to four substituents independently selected fromR^(a); R⁵ is selected from pyridyloxy and C₁₋₈alkyl substituted withpyridyloxy, wherein alkyl is optionally substituted with one to foursubstituents independently selected from R^(a), and pyridyl isunsubstituted or substituted with one to three substituents selectedfrom R^(h), each R^(a) is independently selected from: (1) —OR^(d), (2)—NR^(c)S(O)_(m)R^(d), (3) halogen, (4) —SR^(d), (5)—S(O)_(m)NR^(c)R^(d), (6) —NR^(c)R^(d), (7) —C(O)R^(d), (8) —CO₂R^(d),(9) —CN, (10) —C(O)NR^(c)R^(d), (11) —NR^(c)C(O)R^(d), (12)—NR^(c)C(O)OR^(d), (13) —NR^(c)C(O)NR^(c)R^(d), (14) —CF₃, and (15)—OCF₃; each R^(b) is independently selected from: (1) R^(a), (2)C₁₋₁₀alkyl, (3) oxo, (4) aryl, and (5) arylC₁₋₄alkyl; R^(c) and R^(d)are independently selected from: (1) hydrogen, (2) C₁₋₁₀alkyl, (3)C₂₋₁₀alkenyl, (4) cycloalkyl, (5) cycloalkyl-C₁₋₁₀alkyl, (6) aryl, and(7) aryl-C₁₋₁₀alkyl, each R^(c) and R^(d) may be unsubstituted orsubstituted with one to three substituents selected from R^(h); eachR^(h) is independently selected from: (1) halogen, (2) C₁₋₁₀alkyl, (3)—OC₁₋₄alkyl, (4) —SC₁₋₄alkyl, (5) —CN, (6) —CF₃, and (7) —OCF₃, m isselected from 1 and
 2. 2. The compound according to claim 1, wherein R⁴is selected from: (1) hydrogen, and (2) methyl; and pharmaceuticallyacceptable salts thereof.
 3. The compound according to claim 2, whereinR³ is selected from hydrogen, methyl and ethyl; and pharmaceuticallyacceptable salts thereof.
 4. The compound according to claim 3, whereinR¹ is aryl, wherein aryl is phenyl, wherein each aryl is optionallysubstituted with one to three substitutents independently selected fromR^(b); and pharmaceutically acceptable salts thereof.
 5. The compoundaccording to claim 3, wherein R² is selected from: aryl-C₁₋₄alkyl,wherein aryl is phenyl, and wherein each alkyl is optionally substitutedwith one R^(a) substiruent, and each aryl is optionally substituted withone to three substituents independently selected from R^(b); andpharmaceutically acceptable salts thereof.
 6. The compound according toclaim 3, selected from:(1)N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(3-pyridyloxy)-2-methylpropanamide;(2)N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;(3)N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;(4)N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-pyridyloxy)-2-methylpropanamide;(5)N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;(6)N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-pyridyloxy)-2-methylpropanamide;(7)N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;(8)N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;(9)N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-pyridyloxy)-2-methylpropanamide;(10)N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide;(11)N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide;(12)N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-methyl-2(2-pyridyloxy)propanamide;(13)N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2(2-pyridyloxy)propanamide;(14)N-[2-(3-chlorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-methyl-2(2-pyridyloxy)propanamide;(15)N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-methyl-2(2-pyridyloxy)propanamide;(16)N-[2-(3-bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-methyl-2(2-pyridyloxy)propanamide;(17)N-[3-(4-chlorophenyl)-2-(3-iodophenyl)-1-methylpropyl]-2-methyl-2(2-pyridyloxy)propanamide;(18)N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(6-chloro-2-pyridyloxy)-2-methylpropanamide;(19)N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(20)N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2(R)-(4-trifluoromethyl-2-pyridyloxy)propanamide;(21)N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;(22)N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(23)N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(24)N-[2-(3-bromo-5-fluorophenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(25)N-[2-(3-chlorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;(26)N-[2-(3-chlorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(27)N-[2-(3-bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(28)N-[3-(4-chlorophenyl)-2-(3-trifluoromethylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(29)N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(30)N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;(31)N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(32)N-[2-(3-bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;(33)N-[3-(4-chlorophenyl)-2-(3-cyano-5-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(34)N-[2-(3-cyano-5-fluorophenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(35)N-[3-(4-chloro-3-iodophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(36)2-methyl-N-[1-methyl-3(4-methylphenyl)-2-phenylpropyl]-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide;(37)N-[3-(4-methoxyphenyl)-1-methyl-2-phenylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide;(38)N-[3-(4-fluorophenyl)-1-methyl-2-phenylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide;(39)N-[3-(4-cyanophenyl)-1-methyl-2-phenylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide;(40)N-[2-(3-cyanophenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide;and pharmaceutically acceptable salts thereof.
 7. The compound accordingto claim 3, selected from: (1)N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(3-pyridyloxy)-2-methylpropanamide;(2)N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylbutanamide;(3)N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-pyridyloxy)-2-methylpropanamide;(4)N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;(5)N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylbutanamide;(6)N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;(7)N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-pyridyloxy)-2-methylpropanamide;(8)N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide;(9)N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide;(10)N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;(11)N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;(12)N-[2-(3-chlorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;(13)N-[2-(3-chlorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;(14)N-[3-(4-chlorophenyl)-2-(3-iodophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;and pharmaceutically acceptable salts thereof.
 8. The compound accordingto claim 1, wherein: R¹ is phenyl, wherein each phenyl is optionallysubstituted with one or two substituents selected from halogen, methyl,trifluoromethyl, cyano and methoxy; R² is selected from: (1) benzyl, (2)phenylethyl, (3) 3-phenylpropyl, (4) 2-phenylpropyl, wherein each phenylmoiety is optionally substituted with one or two R^(b) substituentsselected from halogen, trifluoromethyl, cyano, methoxycarbonyl, andmethoxy; R³ is selected from: (1) hydrogen, (2) methyl, and (3) ethyl;R⁴ is hydrogen; R⁵ is C₁₋₈alkyl substituted with pyridyloxy, whereineach pyridyl is unsubstituted or substituted with one to threesubstituents selected from R^(h); each R^(h) is independently selectedfrom: (1) halogen, (2) C₁₋₄alkyl, (3) —O—C₁₋₄alkyl, (4) —S—C₁₋₄alkyl,(5) —CN, (6) —CF₃, and (7) —OCF₃; and pharmaceutically acceptable saltsthereof.
 9. The compound according to claim 8, selected from: (1)N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(3-pyridyloxy)-2-methylpropanamide;(2)N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylbutanamide;(3)N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;(4)N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-pyridyloxy)-2-methylpropanamide;(5)N-[3-(4-chlorophenyl)-2-(3-fluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;(6)N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-pyridyloxy)-2-methylpropanamide;(7)N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylbutanamide;(8)N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;(9)N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-pyridyloxy)-2-methylpropanamide;(10)N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide;(11)N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(6-methyl-3-pyridyloxy)-2-methylpropanamide;(12)N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;(13)N-[2-(3-chlorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-methyl-2-(2-pyndyloxy)propanamide;(14)N-[2-(3-bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-methyl-2-(2-pyrldyloxy)propanamide;(15)N-[3-(4-chlorophenyl)-2-(3-iodophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;(16)N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;and pharmaceutically acceptable salts thereof.
 10. The compoundaccording to claim 3, wherein: R¹ ls aryl, wherein oxyl is phenyl;wherein aryl is optionally substituted with one to three substituentsindependently selected from R^(b); R² is aryl-C₁₋₄alkyl, wherein aryl isphenyl, wherein aryl is optionally substituted with one to threesubstituents independently selected from R^(b); R³ is methyl; R⁴ ishydrogen; R⁵ is

wherein pyridyl is unsubstituted or substituted with one to threesubstituents selected from R^(h); each R^(b) is independently selectedfrom: (1) halogen, (2) cyano, (3) trifluoromethyl, (4) trifluoromethoxy,(5) C₁₋₃alkyloxy, and (6) C₁₋₃alkyl; each R^(h) is independentlyselected from: (1) halogen, (2) C₁₋₃alkyl, (3) —CN, and (4) —CF₃;wherein when pyridyl groups are otherwise unsubstituted on the nitrogen,they may optionally be present as the N-oxide; and pharmaceuticallyacceptable salts thereof.
 11. The compound according to claim 10,wherein: R¹ is phenyl, wherein each phenyl is optionally substitutedwith one or two substituients independently selected from R^(b); R² isphenylmethyl, wherein each phenyl is optionally substituted with one tothree substituents independently selected from R^(b); each R^(b) isindependently selected from: (1) halogen, (2) cyano, (3) C₁₋₃alkyloxy,and (4) C₁₋₃aIkyl; each R^(h) is independently selected from: (1)fluoro, (2) chloro, (3) methyl, (4) —CN, and (5) —CF₃; andpharmaceutically acceptable salts thereof.
 12. The compound according toclaim 11, selected from: (1)N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide(2)N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;(3)N-[3-(4-chlorophenyl)-1-methyl-2-phenyl-propyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;(4)N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(6-methyl-pyridyloxy)-2-methylpropanamide;(5)N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(5-trifluoromethylpyridyloxy)-2-methylpropanamide;(6)N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(7)N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(8)N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(9)N-[3-(4-fluoro-phenyl)-2-(3-cyano-phenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(10)N-[3-(4-chloro-phenyl)-2-(N-methyl-anilino)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(11)N-[3-(4-methoxy-phenyl)-2-(3-cyano-phenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;and pharmaceutically acceptable salts thereof.
 13. The compoundaccording to claim 11, wherein R⁵ is:

and pharmaceutically acceptable salts thereof.
 14. The compoundaccording to claim 13 selected from: (1)N-[(3-(4chlorophenyl)-1-methyl-2-phenylpropyl]-2-(5-trifluoromethylpyridyloxy)-2-methylpropanamide;(2)N[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(3)N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(4)N-[3-(4-fluoro-phenyl)-2-(3-cyano-phenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(5)N-[3-(4-chloro-phenyl)-2-(N-methyl-anilino)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;(6)N-3-(4-methoxy-phenyl)-2-(3-cyano-phenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;and pharmaceutically acceptable salts thereof. 15.N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,or a pharmaceutically acceptable salt thereof.
 16. A method of treatingan eating disorder associated with excessive food intake selected fromobesity, bulimia nervosa, and compulsive eating disorders comprisingadministration to a patient in need of such treatment of atherapeutically effective amount of a compound according to claim
 1. 17.The method according to claim 16 wherein the eating disorder associatedwith excessive food intake is obesity.
 18. A composition comprising acompound according to claim 1 and a pharmaceutically acceptable carrier.19. A method of treating obesity comprising administration to a patientin need of such treatment of a therapeutically effective amount of thecompound according to claim
 15. 20. A composition comprising thecompound according to claim 15 and a pharmaceutically acceptablecarrier.